Bias-probe rotation test of vestibular function

ABSTRACT

Apparatus and methods for rotation test stimulus and analysis methods overcome many of the limitations of traditional clinical tests of peripheral vestibular function. An embodiment includes a rotational stimuli applied to the rotational motion for testing that includes two separate components, a bias component and a probe component. The bias component for rotational motion is designed to temporarily turn off vestibular responses in one ear while the responsiveness in the opposite ear is simultaneously evaluated using the probe component of the stimulus. Responses from application of these stimuli are analyzed by isolating and separating the bias response from the probe response. The bias and probe component responses are parameterized by applying curve fits of mathematical functions to the isolated bias and probe component responses. These parameters characterize the patient&#39;s vestibular function.

RELATED APPLICATION

This application claims priority under 35 U.S.C. 119(e) from U.S.Provisional Application Ser. No. 60/441,853 filed Jan. 21, 2003, whichapplication is incorporated herein by reference.

GOVERNMENT INTEREST STATEMENT

The invention arose from work under a contract with the NationalInstitutes of Health, grant no. DC04592. The Government may have certainrights in the invention.

FIELD OF THE INVENTION

This invention relates generally to quantitative assessment ofvestibular function, more particularly to methods and apparatus formedical evaluation of patients with balance and equilibrium complaints.

BACKGROUND OF THE INVENTION

The medical evaluation of patients with balance and equilibriumcomplaints often includes an assessment of their vestibular function.The goal of this assessment is to determine if peripheral vestibularfunction is normal or abnormal. If vestibular function is found to beabnormal, is one ear involved or are both ears affected? How severe isthe abnormality? Is the abnormality stable or fluctuating? Standardclinical tests frequently do not provide adequate answers to one or allof these questions.

Conventional clinical rotation testing typically uses sinusoidal orvelocity step motion with moderate stimulus amplitudes (50-100°/s peakvelocity) to assess vestibular function by providing a naturalrotational stimulus to the semicircular canals and measuring eyemovements evoked by the vestibulo-ocular reflex (VOR). Conventionalrotation testing has good test-retest reliability, but relatively lowsensitivity. Testing sometimes fails to detect a vestibular abnormalityor, if an abnormality is detected, to provide a detailed assessment ofthe severity and/or the side of lesion.

Quantitative assessment of vestibular function relies primarily onmeasurements of reflexive eye movements (i.e. the VOR) evoked by eithernatural or artificial stimulation of the vestibular receptors of theinner ear. Visual acuity is maintained during head movement by thegeneration of compensatory eye movements that maintain the direction ofgaze fixed in space. In the light, the VOR, smooth pursuit, andoptokinetic reflex systems work together to generate these compensatoryeye movements. But in darkness, compensatory eye movements are generatedonly by the VOR. Therefore, measurements of VOR eye movements in thedark (or sometimes using high frequency head motions where visualreflexes are ineffective) provide an indirect means of assessingperipheral vestibular function.

There are four clinical tests of the vestibular system currently in useon a regular basis. They each have limitations in reliability,applicability, diagnostic precision, and costs that the new rotationtest stimulus and analysis method overcome.

There are two main quantitative clinical tests based on VOR measures:caloric and rotation. Rotation testing includes both conventionalpassive rotations (sometimes referred to as slow harmonic accelerationor SHA testing) and active, subject initiated autorotation tests. Morerecently, the “head impulse test” or “Halmagyi head thrust” test hasbecome popular as an easily applied qualitative method for detecting theexistence of bilateral or unilateral vestibular dysfunction. Thesevarious tests, including their advantages and limitations, are describedin more detail below.

Caloric test. The caloric test artificially stimulates the inner earvestibular receptors using either warm-water or cold-water irrigationsof the external ear canals. This evokes eye movements, which aremeasured and compared across ears to determine vestibular asymmetry.Patients are placed in a supine position with the head elevated about30° in a darkened room. This head position places one set of vestibularreceptors, the horizontal semicircular canals, into an earth-verticalorientation. An irrigation creates a thermal gradient across the innerear that stimulates the horizontal canal, primarily by inducing aconvective fluid movement within the distal loop of the canal, andsecondarily, by direct thermal effects. This fluid movement stimulatesreceptor hair cells, which in turn modulate the activity of the 8^(th)nerve afferents that innervate the horizontal canal. A warm waterirrigation results in an increased afferent discharge rate, and a coldwater irrigation causes a decreased discharge rate. The increaseddischarge caused by warm irrigations evokes a sensation of sustainedrotation toward the irrigated ear and evokes a compensatory VOR eyerotation away from the irrigated ear. Cold water irrigations evokeoppositely directed sensations and compensatory eye movements.

“Slow phase” compensatory eye movements are interspersed with “fastphase” eye movements that reset the eye position towards the straightahead gaze position, producing a triangular-shaped eye position waveformreferred to as vestibular-evoked “nystagmus.” To quantify this response,the slow phase and fast phase components are separated from one another.The slow phase component is analyzed by calculating its slope whichgives the slow phase eye velocity (units °/s) for each beat ofnystagmus. The peak velocity is taken as a measure of the responsivenessof the ear to a particular irrigation.

A complete caloric test typically consists of measuring the peakvelocity response to four separate irrigations (both warm and coldirrigations in each of the two ears). These four peak velocity measuresare scored by the calculation of Jongkees' percentage measures of“reduced vestibular response” (RVR), sometimes referred to as canalparesis, and “directional preponderance” (DP) (See reference 35 listedbelow). If responses are significantly different in the two ears(typically RVR greater than 25% difference), the ear with the lowerresponse is typically considered to be abnormal. If all four irrigationsproduce below normal or absent responses, this implies that the patientmay have bilaterally reduced or absent vestibular function. The DPmeasure compares the responses of irrigations that produce right-beatingnystagmus with those that produce left-beating nystagmus. If DP isabnormal (typically greater than 25%), this suggests that somenon-specific uncompensated imbalance of vestibular function is present.

The chief advantage of the caloric test is that each ear is stimulatedindividually. This allows for the identification of reduced vestibularfunction in an ear even though the patient might be well compensated forthe lesion and may not express any other overt signs of an acutevestibular lesion. In addition, the RVR and DP measures are quantitativein nature and can be used to grade the severity of the vestibularasymmetry.

Caloric testing has several significant limitations. The thermalstimulus that reaches the inner ear depends upon many anatomical factors(i.e., temporal bone thickness, dimensions of middle ear space, fluid inthe middle ear space, variation in blood flow) and procedural factorssuch as the technician's skill. As a result, there is high variabilityacross subjects in delivery of the thermal stimulus to the inner ear,due to differences in temporal bone thickness dimensions of middle earspace, fluid in the middle ear space, and variations in blood flow.These factors make it difficult to detect small differences in responsesbetween both ears. The end result is that test-retest reliability ispoor, making the test a poor choice (unsuitable) for tracking changes investibular function over time. In addition, response variability limitsthe detection of small differences in responses between the two ears.The identification of bilateral vestibular loss is also uncertain due tothe wide variations in response amplitudes in a normal population.Finally, the unusual nature of the stimulus (evoking sensations of along duration rotational motion in a supine position that conflicts withgravity cues from the otolith organs of the inner ear) often provokesnausea in subjects (poor tolerance by subjects) susceptible to motionsickness.

Conventional Rotation Test. The conventional rotation test involves apatient being rotated upright in a clinical rotation chair in acompletely dark room. The chair is rotated about an earth-vertical axis,with rotations of moderate amplitude (50-100°/s peak velocity). Thetypical rotations are sinusoidal, with frequencies ranging from 0.01 to1.0 Hz. Rotational velocity step stimuli and sometimes pseudorandom orsum-of-sines stimuli are also used.

Rotation testing differs from caloric testing in that a naturalrotational stimulus, which stimulates both ears simultaneously, is usedto evoke compensatory VOR eye movements. Patients are tested in acompletely dark room to eliminate visually generated eye movements.During testing, they are seated upright in a chair mounted on aservo-controlled motor. The motor delivers accurately controlledrotational motions of the chair about an earth-vertical axis. Thismotion stimulates primarily the horizontal semicircular canals in bothears. In a subject with normal vestibular function, a rotation towardsthe right causes an increased neural discharge rate in 8^(th) nerveafferents innervating the right side horizontal canal, and a decreaseddischarge rate in afferents innervating the left horizontal canal. Theopposite occurs for rotations to the left. The central nervous system(CNS) uses this “push-pull” neural activity in the two ears to generateVOR eye movements in a direction opposite to the head rotation.

Conventional rotation testing uses rotations with moderate amplitudes(50-100°/s peak velocity). The motion profiles typically are sinusoidalwith frequencies ranging from 0.01 to 1.0 Hz [54,59]. Rotationalvelocity step stimuli [5,32], and sometimes pseudorandom or sum-of-sinesstimuli are also utilized [10,47]. Rotation-evoked nystagmus is analyzedin a manner similar to caloric-evoked nystagmus. The nystagmus isseparated into slow and fast phase components. The slope of thecompensatory slow phase component provides a measure of the slow phaseeye velocity over time. With sinusoidal stimulation, this slow phase eyevelocity component is sinusoidally modulated at the stimulus frequency.A sinusoidal curve fit to the eye velocity gives quantitative measuresof the VOR response that include: VOR gain (response amplitude dividedby stimulus amplitude), VOR phase (timing of the response relative tothe stimulus), VOR bias (average value of slow phase eye velocity over acomplete stimulus cycle), and VOR gain asymmetry (comparison of VOR gainduring rotation to the right versus rotation to the left). Theseresponse parameters vary as a function of the stimulus frequency, anddeviations from the normal pattern are indicative of different types ofvestibular dysfunction. For example, normal VOR gain with abnormal phaseadvance at lower test frequencies, and normal response symmetry isassociated with a well compensated unilateral vestibular loss. ReducedVOR gain with abnormal phase advance and normal symmetry indicates abilateral vestibular loss with the reduction in gain related to theseverity of the bilateral loss.

The natural stimulus used by rotation testing, and the precise meansavailable for delivering the rotational stimulus, provide severaladvantages over caloric testing. First, the test-retest reliability ofrotation testing is good, making rotation testing amenable to trackingfunction over time. Second, the rotation test VOR gain measure has alimited range of normal values, making rotation testing particularlyuseful in assessing bilateral loss of vestibular function. Third, forsinusoidal rotation tests, the repetitive nature of the stimulus affordsgreat opportunity to use averaging to improve test reliability and thepossibility to obtain useful results from partially corrupted datarecords. Fourth, rotation testing is well tolerated by nearly allpatients and only rarely evokes nausea.

The chief disadvantage of rotation testing is that it often does notprovide reliable information (inability to provide reliable information)about which ear is abnormal in a patient with unilateral vestibulardysfunction. There are two main reasons for this failure. First, animalstudies indicate that the 8^(th) nerve vestibular afferents have a highresting discharge rate averaging about 90 impulses/s. Therefore, for themoderate stimulus amplitudes used in conventional rotation testing, eachear is able to accurately encode bidirectional head rotations withoutdriving the discharge rate of a significant number of neurons to zeroduring any portion of the sinusoidal stimulus cycle. That is, even ifvestibular function is completely absent in one ear, the other ear isable to accurately encode bidirectional head movements, and the CNS istherefore able to generate an accurate VOR. Second, the CNS is able tocompensate for the acute effects of a unilateral loss of vestibularfunction which might otherwise be used to identify the existence of aunilateral vestibular deficit. Specifically, an acute loss of vestibularfunction results in a strong “spontaneous nystagmus.” This nystagmusoccurs because the CNS normally compares the neural activity in the twoears and generates compensatory eye movements proportional to thedifference in activity between the two ears. This spontaneous nystagmustypically diminishes over a time course of several days as the CNSrebalances the central VOR neural mechanisms. Once this rebalancing isachieved, only minor signs of vestibular dysfunction remain in theresults of conventional rotation tests (specifically, low frequencyphase advance, and occasionally, gain asymmetries), and even these minorsigns have not been found to reliably indicate the side of the lesion.

A second important limitation in rotation testing is its poorsensitivity in detecting a compensated partial unilateral vestibularloss (inability to reliably identify any abnormality in patients whohave only a partial loss of vestibular function). A recent studydemonstrated that VOR gain measures from rotation tests using bothvelocity step and sum-of-sines stimuli were uncorrelated with theseverity of unilateral vestibular dysfunction as characterized by thecaloric RVR measure (See reference 57 listed below). The mean VOR timeconstant, determined from velocity step responses and indirectly fromresponses to sum-of-sines stimuli, did show a consistent decline withincreasing caloric RVR. However, the wide variability of resultsindicate that many patients with a 40-60% caloric RVR, and some with a60-80% RVR, would not be distinguished from a normal population usingconventional rotation testing. In addition, neither of these rotationtests provided a reliable indication of the side of vestibular loss,except in the 80-100% RVR patient group where velocity step rotationsshowed a small asymmetry between VOR time constants determined duringrotations toward and away from the absent side.

A third limitation of conventional rotation testing is the ambiguitybetween rotation test results in patients with a partial bilateral lossand a compensated unilateral loss (inability to distinguish betweenpatients with a partial bilateral vestibular loss and a compensatedunilateral vestibular loss of function). Both abnormalities produce areduction in the VOR time constant and, equivalently, a low frequencyphase advance. A partial bilateral vestibular loss may cause only a mildreduction in VOR gain such that the VOR gain may remain within thenormal range while the VOR time constant is reduced. This pattern ofnormal gain and reduced time constant is indistinguishable from acompensated unilateral vestibular loss pattern.

Autorotation Test. In the autorotation test, the patient rotates thehead side-to-side in synchrony with an audio tone cue while viewing afixed visual target. The autorotation test evaluates the VOR at higherfrequencies of head rotation (2-6 Hz) than those in conventionalrotation tests. Testing has become standardized using commerciallyavailable systems. Tests are performed in the light with the subjectinstructed to gaze at a fixed visual target. An audio tone cues the testsubject to oscillate his/her head in time with the tone. The tone cuebegins at 0.5 Hz and continuously increases to 6 Hz in about 20 s. Headmovements at lower frequencies are used to calibrate the eye movementrecordings, and higher frequency VOR responses are quantified usingspectral analysis techniques to calculate response gain and phase atfrequencies of 2 to 6 Hz. Deviations of gain and phase responses fromnormal ranges are indicative of abnormal vestibular function.

Autorotation tests evaluate the VOR in a frequency range higher thaneither caloric or conventional rotation tests. Since VOR function inthis higher frequency range is important for maintenance of clear visionduring head movements, autorotation testing provides physiologicallyrelevant information related to gaze stability. The equipment for thistest is inexpensive and portable, particularly compared to conventionalrotation testing. There have been claims that this test has highsensitivity, with some patients showing abnormalities on autorotationtests even though caloric results were normal.

Although this test has been in use for over 10 years, there is littleconsensus regarding its utility and reliability. A recent study (Seereference 27 listed below) investigated autorotation test reliability in12 normal subjects and concluded that “Unfortunately, the test-retestreliability of the VAT [vestibular autorotation test] is poor, andtherefore it cannot be used routinely.” This result, however, wasdisputed by the originator of the VAT system (See reference 44 listedbelow). Potential factors contributing to poor reliability include: eyemovement recording artifacts caused by rapid head movements (high headaccelerations), imperfect measurements of head movements (imperfectmonitoring of head motion) that produce inaccurate evaluations ofvestibular function, inconsistent ability of subjects to achieve regularoscillations at higher frequencies, and analysis artifacts introduced byfast phase eye movements. Finally, the scientific literature onautorotation has focused on the detection of abnormal responses, butlittle information (little research) is available about the test'sability to localize vestibular dysfunction to one or both ears and toquantify the magnitude of the deficit.

Head impulse test. In the head impulse test, an examiner rotates apatient's head with a rapid, high acceleration rotation though an angleof about 20-30° while the patient attempts to maintain higher gaze on afixed target. The examiner looks for corrective eye movements followingthe head rotation, indicating that vestibular function is deficient andunable to generate VOR eye movements that fully compensate for the headrotation. Typically, the rotation is about the head's vertical axiswhich stimulates primarily the horizontal canals. The patient attemptsto maintain his/her gaze fixed on a target during this maneuver. Inpatients with severe canal paresis, the rotation towards thedysfunctional ear or ears produces an inadequate compensatory VOR. Thisinadequate VOR causes the eyes to move off target, with the result beingthat a visually guided corrective saccade is generated to reacquire thetarget at the conclusion of the head rotation. The presence of thiscorrective saccade is a convenient qualitative clinical sign indicatingabnormal canal function. Alternatively, if eye movements are recordedduring head rotations, the gain of the VOR can be calculated and used asan indicator of VOR function.

The main advantage of head impulse testing is that the qualitativeversion of the test (i.e. using the presence of a corrective saccade asa sign of abnormality) can be performed by a knowledgeable practitionerwith no equipment. In cases where patients were known to have a completeunilateral loss of vestibular function, the test has been shown to have100% sensitivity and specificity. In addition, recent research indicatesthat this technique can be extended to include head rotations aboutoblique axes that allow for evaluation of the vertical semicircularcanals.

The chief disadvantage of head impulse testing is that it has recentlybeen shown in a study to have poor sensitivity in cases of less severecanal paresis (See reference 7 listed below). This blinded studycompared the results of conventional caloric testing with head impulsetesting. In patients with severe canal paresis (75-100% RVR on calorictesting), head impulse testing showed abnormal results in 77% of thesepatients. However, head impulse testing revealed abnormalities in only9.5% of patients with moderate paresis (50-75% RVR) and 0% of patientswith mild paresis (25-50% RVR). Overall, it was concluded that headimpulse testing was useful in detecting severe paresis, but could notserve as a replacement for the caloric test. Major limitations are that:(1) it doe not adequately identify mild-to-moderate vestibulardysfunction in a single ear, and (2) the test cannot be used in patientswith any limitations in neck mobility (e.g. limitations due to whiplash,arthritis).

Perhaps the sensitivity of head impulse testing could be improved by theuse of controlled rotations and accurate eye movement recordings thathave been applied in research studies. However, clinical application ofthese improved techniques is problematic for two reasons. First, bettercontrol of rotations would probably require whole body rotations. Arotation device to accomplish this would need high torques to generatethe high accelerations required for these tests. Rotation devices thatare currently in most clinical vestibular laboratories do not haveadequate torque. Second, the short duration of the head impulse requiresan accurate method of recording eye movements at a high sampling rate.Currently, the search coil technique seems to be the only adequatetechnology available. However, search coils are inconvenient to apply ina clinical setting, have some risk associated with their use (i.e.corneal injury), and can only be used for short time periods.

Finally, patients with neck injury or other limitations in neck mobilitycannot be tested using rapid head on body rotations. Patients in thiscategory would include patients with balance complaints associated withaccidents causing whiplash injuries, and elderly patients with limitedmobility due to arthritic conditions.

REFERENCES

The following references provide additional background with respect tovestibular functions, related material, and the testing thereof:

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All publications listed above are incorporated by reference herein, asthough individually incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments, aspects, advantages, and features of the present inventionwill be set forth in part in the description which follows, and in partwill become apparent to those skilled in the art by reference to thefollowing description of the invention and referenced drawings or bypractice of the invention. The aspects, advantages, and features of theinvention are realized and attained by means of the instrumentalities,procedures, and combinations particularly pointed out in theseembodiments and their equivalents.

FIG. 1 depicts a block diagram of an embodiment for a system having adevice to rotate a subject to be tested and a motion control to controlthe motion of the device, in accordance with the teachings of thepresent invention.

FIG. 2 illustrates an embodiment for a two-sine rotational stimulus, inaccordance with the teachings of the present invention.

FIG. 3A illustrates an embodiment of an acceleration pulse, step, andsinusoidal for a pulse-step-sinusoidal (PSS) rotational stimulus, inaccordance with the teachings of the present invention.

FIG. 3B illustrates an embodiment of a velocity waveform for apulse-step-sinusoidal rotational stimulus, in accordance with theteachings of the present invention.

FIG. 4A illustrates an embodiment of a 2-sine stimulus waveform, inaccordance with the teachings of the present invention.

FIG. 4B illustrates an embodiment of a schematic response the 2-sinestimulus waveform of FIG. 4A in a normal subject, in accordance with theteachings of the present invention.

FIG. 4C illustrates an embodiment of a schematic response the 2-sinestimulus waveform of FIG. 4A in a right side unilateral loss subject, inaccordance with the teachings of the present invention.

FIG. 5 shows a block diagram used to simulate VOR responses of anembodiment for testing, in accordance with the teachings of the presentinvention.

FIGS. 6A-6F show the simulated VOR output (simulated VOR slow phase eyevelocity response to a 2-sine stimulus in normal and left unilateralloss subjects) for the simulation of FIG. 5, in accordance with theteachings of the present invention.

FIGS. 7A-7E show the portion of the simulated VOR eye velocity relatedto the high frequency probe component of a 2-sine rotational stimulusfor the embodiment of the simulation of FIG. 5, in accordance with theteachings of the present invention.

FIGS. 8A-8F show a VOR slow phase horizontal eye velocity data recordedfrom one representative normal subject and four unilateral vestibularloss subjects in an embodiment using a 2-sine stimulus, in accordancewith the teachings of the present invention.

FIGS. 9A-9F show a modulation of a VOR response to the probe componentwith the VOR slow phase velocity data filtered using a 0.5 to 5 Hzbandpass filter from the one representative normal subject and the fourunilateral vestibular loss subjects of

FIGS. 8A-8F in an embodiment using a 2-sine stimulus, in accordance withthe teachings of the present invention.

FIG. 10A depicts a block diagram of an embodiment for analysis of aprobe component, in accordance with the teachings of the presentinvention.

FIG. 10B illustrates data from a subject of FIGS. 9A-9F corresponding tothe block diagram of FIG. 10A, in accordance with the teachings of thepresent invention.

FIG. 11 shows a plot of the modulation factor, m, for the three normaland four unilateral loss subjects of the experiment related to FIGS.8A-8F and FIGS. 9A-9F as a function of the bias component stimulusamplitude, in accordance with the teachings of the present invention.

FIG. 12 depicts a block diagram of an embodiment of a method to analyzethe bias components of the 2-sine stimulus, in accordance with theteachings of the present invention.

FIG. 13 shows an embodiment for a input-output relationship generatedaccording to the embodiment in FIG. 12, in accordance with the teachingsof the present invention.

FIG. 14 shows the results of an embodiment of the input-output analysisof FIG. 12 for the four unilateral loss subjects and two normal subjectsof FIGS. 8A-8F, in accordance with the teachings of the presentinvention.

FIGS. 15A-15D show the results of simulation analyses using embodimentsfor the probe analysis and input-output analysis procedures of FIGS. 10Aand 12, in accordance with the teachings of the present invention.

FIGS. 16A-16C show embodiments of the stimulus acceleration, velocity,and simulated semicircular canal afferent discharge rate profiles for aPSS stimulus, in accordance with the teachings of the present invention.

FIG. 17A shows an embodiment for step component measures for a testusing PSS rotational stimulus, in accordance with the teachings of thepresent invention.

FIG. 17B shows an embodiment for sine component measures for a testusing PSS rotational stimulus, in accordance with the teachings of thepresent invention.

FIGS. 18A-18B show eye movement data in normal subjects measured in thedark and measured with a light fixation for an embodiment of a PSSrotational stimulus, in accordance with the teachings of the presentinvention.

FIGS. 19A-19B show eye movement data in subjects with unilateralvestibular loss measured in the dark and measured with a light fixationfor an embodiment of a PSS rotational stimulus, in accordance with theteachings of the present invention.

FIGS. 20A-20B show response parameters obtained from a fixation testperformed on subjects with normal vestibular function and patients withunilateral vestibular loss for an embodiment of a PSS rotationalstimulus, in accordance with the teachings of the present invention.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that the embodiments may be combined, or that otherembodiments may be utilized and that structural, logical and electricalchanges may be made without departing from the spirit and scope of thepresent invention. The following detailed description is, therefore, notto be taken in a limiting sense.

In various embodiments, methods and apparatus for new rotation teststimulus and analysis methods overcome many of the limitations ofconventional clinical tests of peripheral vestibular function, such asthe four clinical tests described above; These embodiments provide a setof clinical tests that aid in the diagnosis of patients exhibitingsymptoms of dizziness and balance instability, by determining whetherinner ear (vestibular) asymmetries exist and, if so, identifying whichear is involved and the severity of the asymmetry. Embodiments of thesemethods and apparatus provide for new testing that delivers precise,repeatable stimuli to the vestibular system, can identify the existenceof asymmetric vestibular function even in well compensated subjects, canidentify which ear is dysfunctional, is well tolerated by most testsubjects, can be performed in patients with limited neck mobility, anddoes not require active participation by the test subject.

Embodiments include a set of test stimuli and associated analysismethods that can be used to characterize an asymmetry of inner ear(vestibular) balance function. Various embodiments are based on anunderlying principle that vestibular responses in one ear can be turnedoff, to allow responses in the other ear to be evaluated. In anembodiment, this is accomplished using a novel 2-component stimulus thatis designed to control the motion of a conventional clinical rotationchair (a device that rotates a seated patient about a vertical axis).

FIG. 1 depicts a block diagram of an embodiment for a system 100 havinga device 110 to rotate a subject to be tested and a motion control 120to control the motion of the device 110.

In this embodiment, stimuli are provided to device 110 to turn offvestibular responses in one ear of the subject, while allowingvestibular responses in the other ear to be evaluated. In an embodiment,device 110 is a clinical rotation chair. In an embodiment, device 110and motion control 120 are integrated. In an embodiment, system 100 is aclinical rotation chair. In an embodiment, rotation of device is aboutan earth-vertical axis with a subject's head oriented 20° nose down fromReid's plane to place the horizontal canal plane perpendicular to theaxis of rotation. Medical centers and clinics that specialize indiagnosing balance disorders usually have conventional clinical rotationchair systems. Several medical equipment companies manufacture thesesystems. Embodiments for the rotation test and analysis may beincorporated into these existing systems by modifying the software thatcontrols the movement of the chair in which the patient, subject, isseated and analyzes the evoked eye movements. In most cases,modifications to the existing rotation chair equipment (motors, eyemovement recording equipment) would be minimal. In an embodiment, thenovel rotation test and analysis may be incorporated into the clinicalrotation chair systems at the time of manufacture, at a nominal cost,since the expense would not involve any new equipment but rather thenovel programming of the rotation chair systems to include the newstimulus and analysis.

In various embodiments, tests are performed with the subject seatedeither in a completely dark room, or in an otherwise dark room exceptfor a small illumined visual target on which the subject visuallyfixates and that rotates with the subject. For tests in the dark,rotational motion stimulates the vestibular motion sensors in the innerear, and information from these motion sensors is used by the centralnervous system to generate eye movements though a reflex known as thevestibulo-ocular reflex (VOR). For tests with the fixation light, visualinformation is used by the central nervous system to partially suppressthe VOR eye movements evoked by the rotational stimulus. For both ofthese tests, eye movements are recorded and analyze, to obtain measuresthat characterize the symmetry of responses to rightward- andleftward-directed rotational motions. A significant asymmetry of theseresponses indicates that vestibular function is not equal in the twoears, and they also provide information about which ear is deficient andthe extent of the deficiency.

An embodiment includes a first type of rotational stimuli applied to therotational motion for testing. Another embodiment includes a second typeof rotational stimuli applied to the rotational motion for testing. Eachtype concludes two separate components referred to as the “bias” and“probe” components. The bias component waveform has a high-amplitude andlong duration rotational motion, while the probe component has alow-amplitude and high-frequency motion. The bias component forrotational motion is designed to temporarily turn off vestibularresponses in one ear while the responsiveness in the opposite ear issimultaneously evaluated using the probe component of the stimulus. Forexample, rotational motion toward the right excites activity in thehorizontal semicircular canal of the right ear (the vestibular motionsensor most affected by rotation when the head is in an uprightposition). This rotational motion toward the right inhibits activity inthe left ear's horizontal semicircular canal. The bias componentamplitude is designed to be large enough to completely inhibit theactivity in the left horizontal canal during a portion of the rightwardmotion of the chair. When the left-side activity is completelyinhibited, the left side motion receptor is unable to encode informationrelated to the probe component motion. If the right side horizontalcanal function is normal, the probe component motion is encoded by thisear and VOR eye movements related to the probe component are generated.However, if right-side horizontal canal function is absent, then neitherear is able to encode the probe component motion, and no VOR eyemovements related to the probe component are generated. The absence ofVOR eye movements related to the probe component is indicative of theabsence of right-side vestibular function.

In an embodiment using the first type of rotational stimulus, the firstrotational stimulus is designed to operate with lower torque motorscommonly used in conventional clinical rotation test systems. In anembodiment, the first type of rotational stimulus is a two-sinestimulus. This first type of rotational stimulus includes two sinusoidalcomponents, as shown in FIG. 2. In an embodiment of the two-sine, or2-sine, stimulus, the bias component, or bias, is provided by a lowfrequency and high amplitude sinusoidal waveform relative to the probecomponent, or probe, which is added to the bias having a higherfrequency and lower amplitude sinusoidal waveform than the bias. In anembodiment of the two-sine, or 2-sine, stimulus, the bias component, orbias, is provided by a low frequency (0.1 Hz or less) and high amplitude(150-250°/s peak velocity) sinusoidal waveform. The probe is added tothe bias and includes a higher frequency (about 1 Hz) and loweramplitude (10-20°/s peak velocity) sinusoidal waveform.

In an embodiment using the second type of rotational stimulus, thesecond rotational stimulus uses a higher torque motor and thus its usewould currently be limited to facilities that have chairs with highertorque motors. However, the second rotational stimulus produces a longerperiod of inhibition, which allows for a longer evaluation period, andbetter opportunity to assess the function of each ear. Therefore, thesecond rotational stimulus may provide better indication of asymmetry.In an embodiment, the second type of rotational stimulus is apulse-step-sine, or PSS stimulus which includes a pulse, step, andsinusoidal waveforms, as shown in FIGS. 3A-3B. In an embodiment of thePSS stimulus, the bias component, or bias, includes 2 parts: ashort-duration acceleration pulse waveform, followed by a loweramplitude, longer duration acceleration step waveform. The probecomponent, or probe, has a sinusoidal waveform. In an embodiment, theprobe waveform is added to the acceleration step portion of the biascomponent. In an embodiment using the PSS stimulus, the bias componentincludes a short-duration, acceleration pulse (about 400°/s² amplitudelasting about 1 s), followed by a lower amplitude, longer durationacceleration step (about 30°/s² amplitude lasting about 4 s). The probecomponent has a sinusoidal waveform (about 1 Hz with 20°/s peakvelocity), which is added to the acceleration step portion of the biascomponent.

In an embodiment, a set of computer algorithms that are used to analyzethe eye movements evoked by embodiments of the rotational stimuli. Theprinciple of the analysis algorithms is that responses to the bias andprobe components of the stimulus are isolated from one another andseparately analyzed. Both of these bias and probe component analysesprovide quantitative measures relevant to the determination ofvestibular function in each ear.

The limitations of the existing clinical tests discussed above motivatedthe development of a new test based on a novel rotational stimulus. Therotational stimuli are designed to take advantage of the 3D arrangementof the three pairs of semicircular canals in the two ears, and thephysiological properties of the 8th nerve afferents innervating eachsemicircular canal. Each canal can be considered to be a fluid filledring lying in a plane with a specific orientation in the head, and withrespect to the other canals. Each canal plane can be defined by a vectorperpendicular to that plane. For a given head rotational velocitycharacterized by a vector aligned with the axis of rotation, afferentnerves innervating a canal will generate a response that depends on boththe magnitude of the rotation and the orientation of the head rotationvector relative to the canal vector. Specifically, each canal respondsonly to the component of the head rotation vector aligned with the canalvector (i.e. the projection of the head rotation vector onto the canalvector).

Semicircular canal orientation. The canals in opposite ears arepair-wise oriented and they operate in a push-pull manner. Thehorizontal canals in the two ears lie in approximately the same, roughlyhorizontal plane. A head rotation towards the left (herein, a positiverotation by convention) causes an increase in discharge rates of allleft canal afferents, and a decrease in discharge rates of all rightcanal afferents. A head rotation to the right produces the oppositeresult. The remaining two pairs of vertical canals (left anterior-rightposterior, and right anterior-left posterior) are oriented approximatelyperpendicular to the horizontal canal pair, perpendicular to oneanother, and about 45° with respect to the midline. A perfect mutuallyperpendicular organization of canal pairs would allow for stimulation ofonly one set of canals at a time if the head were positioned with theaxis of rotation collinear with the orientation vector for that canalpair. However, in reality, both the perpendicular organization betweencanal pairs and the coplanar orientation within canal pairs is onlyapproximate. The extent of this misalignment is of interest since it islikely to influence the sensitivity of the proposed new rotation test.

Semicircular canal afferent physiology. Head rotational motion isencoded by a change in the discharge rate of canal afferents from theirresting rate. Primary afferents exhibit a variety of dynamics, but canbe approximately represented by a first order high pass filter with atime constant of 4 to 7 s (considering the input to be rotationalvelocity). Typical canal afferents in the squirrel monkey have restingdischarge rates of about 90 spikes/s. The discharge rate in humans isunknown, but presumably is similar to the monkey.

The existence of a high resting discharge rate means that each canalafferent can encode both positive and negative velocities. However,depending on the sensitivity of a given afferent, a large enoughrotation in the inhibitory direction can silence neural activity in thatafferent. Once silenced, that afferent is no longer proportionallyencoding the rotational motion. In a subject with functional canals inboth ears, rotational motion that inhibits neural activity in onecanal's afferents excites activity in the opposite ear's paired canal.Since excitatory neural activity can achieve high rates (350-400spikes/s) before saturating, the overall change in activity in pairedcanals (e.g. the difference between left and right side canal activity)monotonically encodes the amplitude of the rotational stimulus. However,the same is not true if vestibular function in one ear is absent. Inthis case, for horizontal plane rotations toward the bad ear, the neuralactivity in the horizontal canal of the good ear will decrease,silencing an increasing proportion of the afferents as the rotationalvelocity increases. In contrast, during rotations toward the good ear,the rotational motion is accurately encoded by the increasing dischargerate of the afferents in the only functional horizontal canal. Thequestion is how to design a rotational stimulus that can demonstrate theexpected asymmetry associated with unilateral vestibular dysfunctionwithout requiring excessive acceleration or velocity.

In an embodiment, a stimulus is provided to take advantage of peripheralnonlinearities. Push-pull action of semicircular canal pairs results inmaximal excitation of afferents in one canal and maximal inhibition ofthe canal afferents in the opposite ear. Canal afferents are more easilydriven to cutoff (zero discharge rate) than to saturation (maximaldischarge rate). Once afferents are driven to cutoff, they cannot encodea change in rotational motion.

Various embodiments are constructed using the hypothesis that unilateralvestibular dysfunction can be characterized using a clinically practicalrotational stimulus that minimally includes two components. A 2-sinestimulus and collected data is described below to illustrate theprinciple of this new type of stimulus. It is anticipated thatembodiments as described herein can be extended to other stimulusconfigurations, including a three-component stimulus. In an embodiment,a three-component stimulus includes a PSS stimulus.

In an embodiment, a two-sine stimulus includes two sinusoidalcomponents. The first component is the low frequency bias component andthe second component as the high frequency probe component. In anembodiment, the purpose of the bias component is to generate a largecyclic shift in the discharge rate of afferents innervating one canalpair using a low frequency (for example 0.1 Hz), higher amplituderotation. A high amplitude, low frequency bias component is used todrive the activity in one canal to zero during a portion of eachstimulus cycle. Based on animal studies, in an embodiment, a 0.1 Hzsinusoidal rotation with a 150-250°/s peak velocity is taken to be ofsufficient magnitude to drive horizontal semicircular canal activity tozero.

The probe component is added to the bias component to provide the 2-sinestimulus. In an embodiment, the purpose of the probe component is totest the sensitivity of the system during different portions of the 10 speriod of the bias component using a high frequency, low amplitudesinusoid (1 Hz, 20°/s in an embodiment). A low amplitude, high frequencyprobe component is used to test the ability of the vestibular system toencode this probe component throughout the entire stimulus cycle. Ifcanal function is absent in one ear, and the bias component rotationdrives the canal activity of the remaining good ear to zero, then motiondue to probe component will not be encoded and VOR eye movements relatedto the probe component will be absent. For horizontal semicircularcanals and VOR, the probe component response will be reduced or absentduring the bias component rotation toward the dysfunctional ear. Use ofa 1 Hz, 20°/s sinusoidal probe motion provides a good compromise betweenadequate signal-to-noise and motor torque requirements.

FIGS. 4A-C shows a schematic response to a 2-sine stimulus 400 (FIG. 4A)in a normal subject 410 (FIG. 4B) and in a right side unilateral losssubject 420 (FIG. 4C). VOR eye movements do not show modulation relatedto the high frequency probe component during rotations toward thedysfunctional ear in the unilateral loss subject. If the amplitude ofthe 0.1 Hz component is adequately large, some proportion of afferentsin the right and left horizontal semicircular canals (RHC and LHC) willbe silenced during a portion of the 10 second (10 s) cycle period. In asubject with normal canal function in both ears, it is expected that inthis embodiment the VOR will be related to combined activity in bothears (the simplest possible model for combination is the differencebetween the two canal signals). Therefore, the 1 Hz modulatory influenceof the probe component should be evident in the VOR eye movementsrecorded throughout the 10 s cycle. When a subject with noresponsiveness in the right ear is tested using the same stimulus, someproportion of LHC afferents are unable to encode (due to silencing oftheir discharge) the rotational motion associated with the 1 Hz probecomponent during a portion of the 10 s cycle period when the subject isrotating toward the abnormal ear. Since the RHC encodes no motion atall, it is expected that in this embodiment the 1 Hz modulatory effectsof the probe component will be reduced or absent in the VOR eyemovements during rotations toward the defective ear. In contrast, duringrotations toward the intact left ear, the LHC neural activity is able toencode both the bias and probe components, and the VOR eye movementswill contain a 1 Hz component corresponding to the probe component ofthe stimulus.

In theory, the 1 Hz modulation would only be completely absent ifactivity in all LHC afferents contributing to the VOR were driven tosilence. In practice, it may not be necessary or practical to silenceall activity in order to develop a useful clinical test stimulus.

The magnitude of the rotational stimulus required to drive the dischargerate of afferents to zero depends upon both the resting discharge rateand sensitivity of the canal afferents. These values are unknown inhumans, but are known in some animal models.

In the squirrel monkey, for example, the mean resting discharge rate isabout 90 spikes/s (s.d. 36) and the mean sensitivity to a rotationalacceleration is 2.24 spikes-s⁻¹/deg-s⁻² (range 0.5-4). Taking intoaccount the dynamic properties of the canals, one can predict that anaverage squirrel monkey horizontal canal afferent would be driven tosilence during the peak inhibitory portion of a 0.1 Hz sinusoidalrotation with a peak velocity of 210°/s. Since there is littlecorrelation between resting discharge rate and neural sensitivity, a 0.1Hz rotation with a 210°/s peak velocity should silence about ½ of allhorizontal canal neurons during a portion of the inhibitory half cycleof the stimulus. If human canal neurons have similar properties tosquirrel monkey canal neurons, one would expect to see considerable VORasymmetries in response to the two-component stimulus in patients withabsent or reduced vestibular function in one ear.

The limitations of vestibular function tests discussed previouslyindicate that no single existing test adequately answers the importantdiagnostic questions: 1) Is vestibular function normal or abnormal? 2)If abnormal, which ear or ears are affected? 3) How severe is theabnormality? 4) Is the abnormality stable or fluctuating? The inadequacyof existing tests can be partially resolved by performing multiple testsusing several different methods. But this increases the cost ofobtaining a diagnosis, and increased cost is difficult to justify in thecurrent health care environment. The reality is that physicians oftensettle for a single test (typically the caloric test as part of astandard test battery) with all of its attendant limitations. Somephysicians may choose not to test at all since their experienceindicates that the existing tests have a limited ability to facilitatetheir diagnostic assessment.

Embodiments for methods and apparatus include rotation test proceduresthat overcome poor performance of conventional rotation testing inidentifying unilateral vestibular dysfunction, but maintains all of theadvantages of conventional rotation testing(non-provocative/non-nauseogenic and good test-retest reliability), andtherefore, can address the four diagnostic questions described in theprevious paragraph. In addition, various embodiments take advantage ofexisting low torque rotation test devices already found in most majormedical centers. This permits rapid adoption of embodiments of this newtest into clinical practice. Such embodiments for a rotation testprocedure would effectively eliminate the need for caloric testing,simplify the selection of appropriate diagnostic tests, and eliminateredundant testing. The routine application of various embodiments ofthis test would result in improved diagnosis of unilateral vestibulardysfunction, and therefore, would foster improved treatment of patientswith chronic disabilities that are sometimes associated with unilateralvestibular dysfunction.

Studies

Discussion of results to studies consists of six parts. First is acomputer simulation illustrating the expected VOR responses to the2-sine rotational stimulus described in the previous section withrespect to FIGS. 4A-4C. Second is a demonstration that experimental VORresponses recorded using a 2-sine rotational stimulus are similar to thepredicted simulation results. Third is a description of an embodiment ofa data analysis procedure for parameterizing responses to the probecomponent of the 2-sine stimulus. Fourth are results from the probecomponent parameterization procedure applied to experimental data from 3normal and 4 unilateral loss subjects. Fifth is a description of anembodiment of a procedure for analyzing the bias component response andthe results of applying this procedure to normal and unilateral losssubject data. Sixth is a discussion of the applicability of the proposedstimulus and analysis procedures to subjects with partial unilateralloss of vestibular function.

VOR Simulation.

FIG. 5 shows a block diagram used to simulate VOR responses (implementedin Simulink, The MathWorks, Natick Mass.). Only the right and lefthorizontal canal pair is represented. The simulation 500 provides VORresponse 510 to stimulus 520 and includes 3 weighted afferent channelsin each ear. The weighting provides a rough approximation to adistribution of afferent properties. The input is considered to be headrotational velocity. In an embodiment, each channel includes a high passfilter with a 5 s time constant representing the dynamics properties ofthe canals. In this simulation, each afferent channel is assumed to havethe same resting discharge rate of 90 spikes/s, but the sensitivity ofeach channel varies. The afferent channel with the largest weight of 0.5is assigned an acceleration sensitivity of 2.24 spikes-s⁻¹/deg-s⁻². Theother two channels, each with a weight of 0.25, are assignedsensitivities of 4 spikes-s⁻¹/deg-s⁻² and 1 spike-s⁻¹/deg-s⁻²,respectively. The model parameters are based on physiological measures(for example afferent sensitivities and the mean discharge rate) in thesquirrel monkey (See references 16 and 24 above). A saturationnonlinearity prevents afferent discharges from falling below zerospikes/s. The stimulus is assumed to be rotational velocity. Allchannels pass through a nonlinear element that clips the discharge rateat zero for rotational motions that inhibit the afferents, but permitsunlimited positive discharge rates. Finally, the VOR eye velocityresponse output is assumed to be proportional to the discharge rate ofall right side afferents minus all left side afferents. To simulate acomplete unilateral absence of vestibular function, the sensitivities ofall afferents in one ear are set to zero.

Various 2-sine rotational motions were used as inputs to this model. Inan embodiment, the stimuli consisted of a 0.1 Hz low frequency biascomponent with amplitudes varying from 0°/s to 250°/s in 50°/sincrements. In the embodiment, the high frequency probe component wasalways 1 Hz with a 20°/s amplitude. FIGS. 6A-6F shows the simulated VORoutput (simulated VOR slow phase eye velocity response to a 2-sinestimulus in normal and left unilateral loss subjects) for the embodimentof the simulation of FIG. 5. The bias component stimulus amplitudeincreased from 0 to 250°/s, but the probe stimulus amplitude remainedconstant. This simulated VOR output illustrates that no responseasymmetry is grossly evident when the bias component amplitude was belowabout 100°/s. However, at higher bias component amplitudes, the responsebecame increasingly asymmetric with reduced responses during rotationstoward the absent ear.

FIGS. 7A-7E show the portion of the simulated VOR eye velocity relatedto the high frequency probe component for the embodiment of thesimulation of FIG. 5. Simulated VOR probe responses to a 2-sine stimulusin normal and left unilateral loss subjects. The bias componentamplitude increased from 0 to 250°/s. At higher bias componentvelocities, the response to the probe component decreased duringrotations toward the dysfunctional left ear. The response to the probecomponent was separated from the bias component using a 0.5 to 5 Hzbandpass filter. For normal subjects, the probe component response waspresent throughout the 10 s period corresponding to one cycle of the 0.1Hz bias component, although some “double modulation” distortion occurredat higher bias component amplitudes. This distortion consisted of adecrease in the probe component VOR during the two portions of the 10 sbias component cycle corresponding to the peak bias component velocity.

When the left ear sensitivity was set to zero to simulate a unilateralloss, the high frequency VOR component was present throughout the 10 speriod only when the bias component amplitude was 100°/s and below. Butwhen the bias component amplitude was increased (150 to 250°/s), theprobe component VOR was reduced during the portion of the bias componentcycle corresponding to rotation towards the dysfunctional ear.

Experimental Responses to 2-Sine Stimulation.

Three normal and four unilateral loss subjects were tested using 2-sinestimuli identical to those used in the simulation study described abovewith respect to FIGS. 6A-6F and FIGS. 7A-7F. The unilateral losssubjects included subject UL1, a 66 year old female who had a left sideacoustic neuroma removed by a trans-labyrinthine surgical approach 3years prior to testing, subject UL2, a 46 year old male with a 3 cm leftside acoustic neuroma treated with a “gamma knife” radiation procedure3½ years prior to testing, subject UL3, a 27 year old male with rightside absent vestibular function, as determined by caloric testing(Meningitis contracted during infancy is believed to be the cause ofthis right side loss), and subject UL4, a 47 year old female with aright labyrinthectomy performed 3 months prior to testing as treatmentfor Meniere's disease.

All 4 unilateral loss subjects were well compensated as judged by theirresponses to conventional rotation tests (0.05, 0.2, and 0.8 Hzsinusoidal rotations with 60°/s peak velocity). Three of the fourunilateral loss subjects showed abnormally advanced VOR response phaseat 0.05 Hz (>20° phase lead). The fourth subject's (UL1) phase wasadvanced relative to center normal, but was not outside of theestablished lab normal range. Phase advance is typically the onlyabnormal finding with conventional rotation testing in well compensatedunilateral loss subjects. However, this abnormal finding does notprovide any information regarding the side of the vestibular loss.

All of the test stimuli were well tolerated by the three normal and fourunilateral loss subjects tested to date. No discomfort, disorientation,or motion sickness symptoms were reported throughout the test sessionswhich lasted about 2 hours. Following testing, there were no complaintsof imbalance, and none of the subjects had difficulty walking ormaintaining stance.

FIGS. 8A-8F show the VOR slow phase horizontal eye velocity datarecorded from one representative normal subject and the four unilateralvestibular loss subjects in this embodiment to a 2-sine simulation.These experimental responses are qualitatively similar to the simulationresults (FIGS. 6A-6F). The experimental VOR slow phase eye velocityresponses to 2-sine stimuli with the bias component amplitude increasingfrom 0 to 250°/s. Results are shown for two subjects with a leftunilateral loss (UL1 & UL2), two subjects with a right unilateral loss(UL3 & UL4) and one normal subject (N1). The normal subject showedsymmetric VOR responses for rightward and leftward directed rotationsthat increased with increasing stimulus velocity. The response to the 1Hz probe component for the normal subject was evident throughout theentire 10 s cycle of the bias component.

Three of the four unilateral loss subjects (UL1, UL2, UL4) showedreasonably symmetric responses when the bias component amplitude was50°/s. Responses of the unilateral loss subjects resembled normalsubject responses for bias component amplitudes of 0 and 50°/s. SubjectUL3 began to show some asymmetry even at a 50°/s bias componentamplitude. In contrast to the normal subject responses, the asymmetryincreased for all UL subjects as the bias component amplitude increased.This asymmetry was always such that the VOR eye velocity was reducedduring rotation toward the dysfunctional ear. At higher bias componentamplitudes, the VOR response to the probe component was not uniformthroughout the 10 s bias component cycle, but was reduced during theportion of the bias component cycle when the subject was rotatingtowards the dysfunctional ear. Responses of the unilateral loss subjectsshowed saturation during rotation toward the absent ear at higher biascomponent amplitudes.

FIGS. 9A-9F show the modulation of the VOR response to the probecomponent with the VOR slow phase velocity data filtered using a 0.5 to5 Hz bandpass filter. Experimental VOR probe responses to 2-sine stimuliwith the bias component amplitude increasing from 0 to 250°/s. Resultsare shown for the two subjects with a left unilateral loss (UL1 & UL2),the two with a right unilateral loss (UL3 & UL4), and the one normalsubject (N1) of FIGS. 8A-8F.

VOR modulation of the probe response is diminished during rotationstowards the dysfunctional ear. The unilateral loss subjects showed asystematic modulation of the VOR probe component amplitude over the 10 sbias component cycle. This modulation increased with increasing biascomponent amplitude. In contrast, the normal subject did not show asystematic increase in probe component modulation with increasing biascomponent amplitude. Additionally, the normal subject did not show the“double modulation” evident in the simulated VOR responses at the 200and 250°/s bias component velocities, indicating that the simple modelin FIG. 5 does not fully capture actual VOR behavior. All 3 normalsubjects tested had results similar to those shown in FIGS. 9A-9F.

Analysis

FIG. 10A depicts a block diagram of an embodiment for analysis of aprobe component. The flow diagram for the embodiment of the method shownin FIG. 10A is used to characterize the response to the probe componentportion of the VOR. Example data in FIG. 10B are from subject UL1 ofFIGS. 9A-9F, with a left side unilateral loss, tested with a 200°/s biascomponent amplitude. The analysis includes both standard methodology,typically applied to VOR analysis, and novel methodology used toseparate and analyze the probe response. A video analysis is performed,at 1010, to acquire pupil center coordinates (x_(c), y_(c)) and acalibration is applied, at 1020, to provide a horizontal eye positionand a vertical eye position as a function of the pupil centercoordinates (x_(c), y_(c)). The standard portion of the analysisincludes calculation of eye velocity from eye position data, at 1030,and separation of the slow and fast phases of nystagmus in order toobtain slow phase eye velocity, at 1040. The novel aspects of theanalysis include bandpass filtering to isolate the response to the probecomponent of the stimulus, at 1050, and parameterization of the proberesponse, at 1070. As shown in FIG. 10A, after filtering, at 1050, thefiltered signal may be averaged, at 1060, such as averaging over five0.1 Hz cycles. In an embodiment, the parameterization of the proberesponse uses a curve fit. In an embodiment, the curve fit, the proberesponse fit, to the filtered and averaged VOR data uses the followingequation:<{dot over ({circumflex over (θ)}_(bp) >=A _(p)(1+m cos(ω_(b) t+φ_(b)))cos(ω_(p) t+φ _(p))  (eqn. 1a)<{dot over ({circumflex over (θ)}_(bp) >=A _(p)(1+M(t))cos(ω_(p) t+φ_(p))  (eqn. 1b)In an embodiment, the bandpass response is filtered over a number ofcycles of the bias component. In an embodiment, the bandpass response isfiltered over five 0.1 Hz cycles.

In an embodiment, the curve fit is performed using a constrainednonlinear optimization procedure “const” available in the MatlabOptimization Toolbox (the curve fit actually includes sine and cosinecomponents from which the phase of the response relative to a cosinereference is calculated). This equation represents an amplitudemodulation (AM) operation used to describe communication systems where a“carrier” waveform, represented here by the probe frequency (ω_(p)), ismodulated by a lower frequency waveform using a multiplicativeoperation. In this case the lower frequency modulation occurs at thebias component frequency (ω_(b)). The fit parameters include the probecomponent eye velocity amplitude (A_(p)), and the modulation function,M(t) whereM(t)=m cos(ω_(b) t+φ _(b))with m being a modulation factor, which can vary from 0 to 1,representing the depth of modulation of the probe frequency, the probecomponent phase, φ_(p), and the phase of the modulation waveform, φ_(b).Modulation factor, m, is related to the severity of the unilateralasymmetry. Modulation phase, φ_(b), indicates the side of unilateralloss. In an embodiment, A_(p) equals the 1 Hz probe component eyevelocity amplitude and m equals the modulation factor representing thedepth of modulation of the probe component eye velocity.

FIG. 11 shows a plot of the modulation factor, m, for the three normaland four unilateral loss subjects of the experiment related to FIGS.8A-8F and FIGS. 9A-9F as a function of the bias component stimulusamplitude. It can be seen that at lower bias component amplitudes, thisparameter is unable to distinguish between normal and unilateral losssubjects. However, a clear separation is evident between subject UL3 andnormals at a bias component amplitude of 100°/s, and at 150°/s all fourunilateral loss subjects are distinguishable from normals. Themodulation parameter increases with increasing bias component amplitude.For subject UL3, the modulation parameter saturated at 1 (fullmodulation) for the 200°/s and 250°/s bias component amplitude.

There are two important considerations regarding these preliminaryresults. First, the distortion of the probe component occurred at lowerbias component amplitudes than indicated by the simple simulation modelbased on squirrel monkey afferent properties. This suggests that humanshave either higher canal afferent sensitivity, or lower canal afferentresting discharge rates than the squirrel monkey. Whichever is the case,this apparent difference in physiology is advantageous in designing anew rotation test based on a 2-sine stimulus, since lower and presumablymore tolerable bias component amplitudes should be adequate for the thisnew test. In addition, a lower peak stimulus amplitude evokes lowervelocity eye movements, and this improves the likelihood that slow andfast phase components of nystagmus can be successfully separated fromone another.

Second, two of the unilateral loss subjects shown in FIG. 11 (UL1 andUL4) had modulation factors that reached values of only 0.4 to 0.5 atthe highest bias component amplitudes. Subject UL1's head was in acomfortable upright position during testing, and was not oriented in theapproximately 20° nose down position that is expected to align thehorizontal canals perpendicular to the axis of rotation. Therefore, thefailure to obtain a large modulation factor for this subject at highbias component amplitudes may be due to the contribution of partiallystimulated vertical canals contributing to the generation of horizontaleye movements. An attempt was made to align subject UL4's head formaximal horizontal canal stimulation; however, this alignment was notfully accomplish this due to limitations in procedures. Subsequentdesign of a head restraint system enables the systematic control of thehead alignment.

Additional preliminary data indicates that head orientation does affectthe modulation factor in unilateral loss subjects. For example, forsubject UL4 tested with a bias component amplitude of 200°/s, mincreased from 0.42 to 0.58 with a head tilt of 5° in a directionexpected to bring the horizontal canals into better alignment. Forsubject UL3, also tested with a 200°/s bias component amplitude, mdecreased from 1.0 to 0.81 when the head was reoriented by 5°.Therefore, head orientation appears to be an important factorinfluencing the sensitivity for various embodiments of the rotationtest. The influence of head orientation can be systematicallyinvestigated using both modeling and experimental methods.

With respect to the probe component responses of FIGS. 9A-9F, for thenormal subjects, there was little or no modulation over the course ofthe bias component cycle. The modulation factor, m, increased onlyslightly with increasing bias component amplitude. Further, for thenormal subjects, estimates of the probe-related slow phase eye velocitywere nosiest during the high velocity portions of the bias componentcycle. Increased noise was due to increased high frequency nystagmus.

With respect to the probe component responses of FIGS. 9A-9F, for theunilateral loss subjects, modulation factor, m, increased withincreasing bias component velocity. Probe response amplitude wassmallest for these subjects during bias component rotation toward theabsent ear. For the unilateral loss subjects, estimates of theprobe-related slow phase eye velocity were noisiest during the highvelocity portion of the bias component cycle when the subject wasrotating toward the good ear. This noise likely caused increasedvariability in the estimation of m, and this variability increased withincreasing bias component amplitude.

The VOR responses to the 2-sine stimuli in FIGS. 8A-8F show that theoverall response was quite asymmetric and distorted for the unilateralloss subjects compared to the example normal subject at higher biascomponent amplitudes. For this preliminary data from subjects withcomplete unilateral loss, it appears that a larger amplitude sinusoidalstimulus alone (i.e. without the probe component) would adequatelyidentify the side of the vestibular asymmetry. In the next section,simulation results are used to argue that this may not be the case insubjects with a partial unilateral loss. Nevertheless, at this point, itis reasonable to analyze data in all ways that seem likely to contributeto the identification of asymmetric function.

FIG. 12 depicts a block diagram of an embodiment of a method to analyzethe bias components of the 2-sine stimulus. The flow diagram for theembodiment of the method shown in FIG. 12 shows a procedure to analyzedistortion in the bias component of the 2-sine stimulus. This method maybe related to methods previously used to analyze VOR gain asymmetries.Example data in this figure are from subject UL1 in FIGS. 8A-8F testedwith a 200°/s bias component amplitude. At 1210, slow phase eye velocityand stimulus velocity data are low pass filtered (in an embodiment, alow pass filter having a 0.5 Hz cutoff is used) to remove the probecomponent from both the stimulus and VOR response waveforms. At 1220,the data is averaged over a number of cycles of the bias component. Inan embodiment, the data are then averaged over five 0.1 Hz cycles. In anembodiment, the data are then averaged over consecutive 10 s periodscorresponding to the bias component cycle period. A discrete Fouriertransform is used to estimate the phase of the stimulus and responsewaveforms at the bias component frequency. At 1230, these waveforms arethen time shifted so that they are aligned with a 180° phase shiftbetween them (reflecting the compensatory nature of the VOR). Finally,at 1240, a negatively sloped input-output function is obtained byplotting the eye velocity versus the stimulus velocity. FIG. 13 shows anembodiment for a input-output relationship generated according to theembodiment in FIG. 12. In an embodiment, deviations of this input-outputfunction from a straight line indicate the presence of nonlinear systemeffects, in this case a saturation-type nonlinearity where the eyevelocity is attenuated at higher velocities of rotations toward the earwith absent vestibular function.

FIG. 14 shows the results of an embodiment of the input-output analysisof FIG. 12 for the four unilateral loss subjects and two normal subjectsof FIGS. 8A-8F. All data in FIG. 14 are from a 2-sine stimulus with a200°/s bias component amplitudes. In all unilateral loss subjects,rotations toward the dysfunctional ear produced a clear saturation-typenonlinearity compared to rotations toward the good ear. Consistentestimates of saturation amplitudes were obtained using 200 and 250°/sbias component stimuli, and often with 150°/s stimuli. The normalsubjects had symmetric, although not entirely linear, input-outputfunctions with no saturation.

Previous investigators have quantified similarly determined input-outputfunctions by fitting two line segments to the input-output function withone line segment corresponding to positive stimulus velocities and theother to negative stimulus velocities. The slope of these line segmentsprovide measures of VOR gain for rotations to the right and left. A VORgain asymmetry measure can be obtained from these two gains using theformula 100*(GainR−GainL)/(GainR+GainL). The preliminary results show aclear saturation-type nonlinearity suggest that a two-part linear fitwould not be a good choice. In an embodiment, a better candidate forfitting the input-output data would appear to be some type of saturatingfunction such as:

$\begin{matrix}{\left\langle {\hat{\overset{.}{\theta}}}_{lp}^{\prime} \right\rangle = \frac{K\left( {1 - {\mathbb{e}}^{{- \beta}{\langle\omega_{lp}^{\prime}\rangle}}} \right)}{1 + {\mathbb{e}}^{{- \beta}{\langle\omega_{lp}^{\prime}\rangle}}}} & \left( {{eqn}.\mspace{14mu} 2} \right)\end{matrix}$where <{dot over ({circumflex over (θ)}′_(tp)> is a fit to the low passfiltered bias component eye velocity, <ω′_(lp)> is the low pass filteredbias component stimulus velocity, and K and β are fit parameters relatedto the gain and saturation behavior of the input-output function.Parameter K is the saturation amplitude (°/s), β is the saturation rate,and <ω_(lp)> is the phase aligned bias component of the stimulusvelocity. Since the saturation function given by eqn. 2 is symmetricabout the origin, separate fits of this functional form would berequired for rotations toward the right and left.

An important question is whether or not a 2-sine stimulus can be used toidentify and localize a partial unilateral vestibular lesion. Simulationresults based on FIG. 5 simulation model suggest that it can. Partiallesions were simulated by setting the gains of all afferent fibers inthe left ear to some fraction of their normal value (afferent gains of0.75, 0.5, 0.25, and 0 times normal values to simulate 25%, 50%, 75%,and 100% canal paresis, respectively). The simulation was run using a2-sine stimulus with a 250°/s bias component amplitude and 20°/s probecomponent amplitude. The simulated eye velocity responses were analyzedusing embodiments for the probe analysis and input-output analysisprocedures of FIGS. 10A and 12.

The results of these analyses are shown in FIGS. 15A-15D. Thesesimulation results show effects of increasing levels of unilateralvestibular dysfunction. The center column shows VOR probe componentanalysis of simulated data and the right column shows input-output biascomponent analysis. The probe response shows a clear relationshipbetween the depth of modulation and the magnitude of the vestibularasymmetry. The input-output analysis also shows that the asymmetry ofthe bias component response increases with increasing vestibularasymmetry. However, it is easy to imagine that it would be difficult todetect a 25% or 50% canal paresis from the bias component input-outputanalysis in the presence of relatively small amounts of physiologicalvariability in the eye velocity data. In contrast, the probe componentresponse appears to be more robust. This result is consistent with thefact that the probe component analysis essentially provides anindependent comparison of VOR gain at the peak positive and negativeexcursions of the bias component stimulus. These two peak points in thebias component stimulus cycle are most likely to be influenced by theexistence of asymmetric vestibular function. In contrast, theinput-output analysis of the bias component response is dominated bylarge portions of the input-output function which are likely to besymmetric even though a partial vestibular asymmetry exists.

Based on the preliminary results in subjects with a verified completeunilateral loss of vestibular function, an embodiment using rotationalstimulus appears to be effective in unambiguously identifying the sideof lesion. As can be appreciated by those skilled in the art, additionalwork can be performed to determine optimal stimulus design, investigatefactors that influence test sensitivity and reliability, and apply thevarious embodiments for the rotational test to a larger group ofsubjects with varying levels of vestibular dysfunction.

In an embodiment for testing with a 2-sine stimuli, the frequencycomponents are shown in Table 1. For each of the four frequencycombinations, the amplitude of the bias component is be varied from50°/s to 250°/s in increments of 50°/s while the probe component remainsfixed in frequency and amplitude.

TABLE 1 2-sine stimulus frequency combinations Probe Component Stimulus# Bias Component Frequency (Hz) Freq (Hz) Amp (°/s) 1 0.025 1 20 2 0.051 20 3 0.1 1 20 4 0.1 2 10

A pulse-step-sine (PSS) stimulus, representing a form of 3-componentrotational stimulus, can be applied to produce a large shift in thedischarge rate of the primary afferents, followed by testing at theextremes of the discharge rate shift. The PSS stimulus provides apotentially optimal stimulus for rapidly displacing the afferentdischarge rate, maintaining that discharge rate displacement at aconstant level, and then testing the system. The PSS stimulus includes ashort duration acceleration pulse followed by a lower amplitude, longerduration acceleration step. A sinusoidal probe component is added to theacceleration step. With proper selection of the acceleration pulse andstep components, the afferent discharge rate will theoretically remainat a constant shifted level throughout the duration of the step phase ofthe stimulus. Therefore, the sinusoidal probe component can test thesystem while the afferent discharge rate is at a fixed displacement fromthe resting rate. This is in contrast to a 2-sine stimulus where theafferent discharge rate is continuously changing throughout the biascomponent cycle.

The stimulus acceleration, velocity, and simulated afferent dischargerate profiles for an example PSS stimulus are shown in FIGS. 16A-16C.The trace of FIG. 16A shows the rotational acceleration profile for theexample PSS stimulus. The trace of FIG. 16B shows the velocity profilefor the example PSS stimulus. The trace of FIG. 16C shows a simulatedresponse to the PSS stimulus of an average squirrel monkey canalafferent. Variations in the pulse duration and amplitude determine thedisplacement of afferent discharge rates from resting levels. Theacceleration step amplitude needed to maintain that displaced dischargerate is a function of the preceding pulse parameters and the timeconstant of the afferent nerve fibers. In an embodiment, a 5 s timeconstant is assumed in the stimulus design. The displacement of afferentdischarge from the resting rate, ΔR, is given by:ΔR=S _(aff) A _(pulse)(1—e^(−1p/2τ))  eqn. 3where S_(aff) is the acceleration sensitivity of the afferent, A_(pulse)is the acceleration pulse amplitude of the PSS stimulus, t_(p) isacceleration pulse duration, and τ is the afferent time constant.

As the amplitude of the preceding pulse increases, a larger stepacceleration is needed to maintain a fixed discharge rate. Severalcycles of a sinusoidal motion are added to the step component to providea probe stimulus to test the VOR system while the afferents remain at adisplaced discharge rate. Table 2 shows a series of PSS stimuli witheach subsequent stimulus in the series producing a larger afferentdischarge displacement. In an embodiment, the cycle length for each ofthese 4 stimuli is 10 s. The predicted displacement of afferentdischarge is matched to the peak displacement predicted for the 0.1-1.0Hz 2-sine stimuli with the 0.1 Hz bias component amplitude varying from50°/s to 200°/s.

TABLE 2 PSS stimuli Pulse Step Sine Component Component Component PSSAmp Duration Amp Duration Freq Amp Stimulus (°/s²) (s) (°/s²) (s) (Hz)(°/s²) Cycles 1 400 0.25 9.9 4.75 0.95 20 4.5 2 400 0.51 19.9 4.49 1.020 4.5 3 400 0.78 30.0 4.22 0.83 20 3.5 4 400 1.05 39.9 3.95 0.89 20 3.5

In an embodiment, PSS analysis involves measurement of the amplitude ofthe sine component for rotations to the right and left. An asymmetrymeasure (similar to the VOR gain asymmetry measure used to characterizeconventional rotation test responses) calculated from these amplitudemeasurements would correspond approximately to the modulation factor, m,calculated from the probe analysis for the 2-sine stimuli. If theresponse to the sine component of the PSS stimulus is ignored (by lowpass filtering), the remainder of the PSS slow phase velocity responseshould approximate a square wave (with rounded corners). A displacementof the mean value of this slow phase velocity waveform (mean calculatedover an integer number of cycles) away from zero would be indicative ofan asymmetry of this response, and would correspond approximately to theinput-output analysis of the bias component of the 2-sine stimulus.

For the 2-sine test series, response parameters (e.g. m and parameterssummarizing the asymmetry of input-output functions) may be plotted as afunction of the bias component amplitude, as in FIG. 11 plots of mversus bias component amplitude. Similar plots may be made for measuresderived from the PSS stimuli, with PSS response asymmetry measuresplotted versus an equivalent to the bias component amplitude(specifically, the peak velocity amplitude of the fundamental frequencycomponent of the PSS stimulus).

From the results in FIG. 11, it is anticipated that as the biasamplitude increases, there will be an increasing separation betweenasymmetry measures from normal subjects versus unilateral loss subjects.At each bias component amplitude, the mean, standard deviation, andrange of response parameters for the normal and unilateral loss groupsmay be computed for each of the four different test series given inTable 1 and the PSS series in Table 2. Assuming approximately normaldistributions, but not necessarily equal variances between the groups, a“threshold bias amplitude,” defined as the point where the separationbetween results from the normal and unilateral loss group have a maximum5% misclassification of normal subjects as abnormal and abnormalsubjects as normal (95% specificity and 95% sensitivity), can beestimated. Test series may be compared by their threshold biasamplitudes. The series with the lowest threshold bias amplitude will bepresumed to be the most sensitive test for detecting a unilateralvestibular asymmetry.

Other features of response parameter variation may also be considered.For example, saturation effects can be considered, as shown in themodulation factor data from subject UL3 in FIG. 11. It would bedetrimental to choose a stimulus for clinical use that showed saturationeffects in complete unilateral loss subjects since abnormal subjectswith less than a complete unilateral loss might be indistinguishablefrom complete loss subjects.

Experimental Responses to a Pulse-Step-Sine Rotational Stimulus

In applying the PSS rotational stimulus, the application of thisstimulus takes advantage of peripheral nonlinearities. The push-pullaction of semicircular canal pairs results in maximal excitation ofafferents in one canal and maximal inhibition of the canal afferents inthe opposite ear. Canal afferents are more easily driven to cutoff (zerodischarge rate) than to saturation (maximum discharge rate), and onceafferents are driven to cutoff, they cannot encode a change inrotational motion.

In the PSS stimuli applied, the pulse component provides a rotationalacceleration pulse that drives the activity in one canal toward zeroduring a portion of each stimulus cycle. An acceleration step maintainsthe canal nerve activity at a zero discharge rate throughout theduration of the step component. The sine component is a low amplitude,high frequency sine waveform that is added to the step portion of thestimulus. The sine component tests the ability of the vestibular systemto encode this component throughout the step portion of the stimulus. Ifcanal function is absent in one ear, and the pulse-step components drivethe canal activity of the remaining good ear to zero, then motion due tothe sine component will not be encoded and VOR eye movements related tothe sine component will be absent. For horizontal semicircular canalsand VOR, the sine component response will be reduced or absent duringpulse-step component rotation toward the dysfunctional ear. Use of a 1Hz, 20°/s sinusoidal component motion provides a good compromise betweenadequate signal-to-noise and motor torque requirements.

An experimental application using four different PSS stimuli (Table 2)included ten subjects with normal vestibular function, five subjectswith complete unilateral vestibular loss (three left and two right), andone subject with asymmetric bilateral vestibular loss with the rightside less than the left side. The testing of the subjects includedrotation about earth-vertical axis in the dark and the head orientated20° nose down from Reid's plane to place horizontal canal planeperpendicular to rotation axis. The parameters for the four PSSrotational stimuli were a pulse component having a 400°/s² amplitudewith durations ranging from 0.25 to 1 s, a step component havingamplitudes ranging from 10 to 38°/s² with durations ranging from 4 to4.8 s, and a sine component with either 3.5 or 4.5 cycles ofapproximately 1 Hz sinusoid with 20°/s amplitude (Table 2).

In normal subjects, the responses were symmetric for leftward andrightward directed rotations. Response to the sine component was evidentthroughout both rightward and leftward step components. In unilateralloss subjects, the responses resembled normal subject response forlowest amplitude PSS stimulus. The responses became increasinglyasymmetric with increasing PSS amplitude with loss of the sine responseduring rotation toward the absent ear. In the asymmetric bilateral losssubject, the responses became increasingly asymmetric with increasingPSS amplitude with step component response showing the primaryasymmetry.

Measures for PSS rotational stimulus are generated from slow/fast phaseseparation of eye velocity data and averaging over a number of cycles ofthe bias component of the stimulus, in which the response to thesinusoidal stimulus is isolated from the response to the pulse-stepcomponent.

PSS Bias (or Step) Component Measures.

PSS step component measures are made from average slow phase eyevelocity data obtained from the step portion of the pulse-step-sinestimulus. There are two measures. One is the “step asymmetry” and theother is the “mean response slope.” The step asymmetry parameter gives acomparison of the difference in response gains for rotations that evokeleftward eye movements versus rotations that evoke rightward eyemovements. A “gain” is defined as the ratio of the response velocity tothe stimulus velocity. The equation is shown in FIG. 17A relative to thegraphs for stimulus velocity and VOR slow phase eye velocity, where theparameters in this equation are:

-   -   A_(SL)=average stimulus velocity (units °/s) during the        leftward-moving step portion of the PSS stimulus. The subscript        “S” stands for stimulus and the subscript “L” stands for        leftward.    -   A_(SR)=average stimulus velocity (units °/s) during the        rightward-moving step portion of the PSS stimulus.    -   A_(RL)=average VOR slow phase eye velocity (units °/s) during        the leftward-moving step portion of the PSS stimulus. The        subscript “R” stands for response and the subscript “L” stands        for leftward and refers to the fact that this eye velocity is        the average value measured during the leftward stimulus motion.        The eye velocity is typically directed toward the right during a        leftward stimulus motion.    -   A_(RR)=average VOR slow phase eye velocity (units °/s) during        the rightward-moving step portion of the PSS stimulus. The first        subscript “R” stands for response and the second subscript “R”        stands for rightward and refers to the fact that this eye        velocity is the average value measured during the rightward        stimulus motion. The eye velocity is typically directed toward        the left during a rightward stimulus motion.        The mean response slope parameter is given by the equation:        Mean Response Slope=(S _(RR) −S _(RL))/2,        where S_(RR) is the rate-of-change (i.e. a slope) of slow phase        eye velocity (units °/s²) measured during the rightward-moving        step portion of the PSS stimulus. The first subscript “R” stands        for response and the second subscript “R” stands for rightward        and refers to the fact that this eye velocity is the average        value measured during the rightward stimulus motion. S_(RL) is        the rate-of-change (i.e. a slope) of slow phase eye velocity        (units °/s²) measured during the leftward-moving step portion of        the PSS stimulus. The subscript “R” stands for response and the        subscript “L” stands for leftward and refers to the fact that        this eye velocity is the average value measured during the        leftward stimulus motion.

The mean response slope parameter is a measure that is related to ameasure called the “VOR time constant” that is often obtained fromresponses to a conventional clinical rotation test. The value of apatient's VOR time constant can provide information about vestibulardysfunction. Specifically, a VOR time constant that is less than 5seconds is typically associated with a bilateral loss of vestibularfunction. A time constant of 5 to 6 seconds is often associated with aunilateral vestibular loss. Finally, a time constant greater that about8 seconds suggests normal vestibular function. The relation between theVOR time constant and the mean response slope is that subjects with aVOR time constant less than 5 seconds will have a slope with value lessthan zero. The mean response slope will be equal to zero if the VOR timeconstant is 5 seconds, and the mean response slope will be greater thanzero if the VOR time constant is greater than 5 seconds. Therefore, thisslope parameter provides equivalent information to that provided by animportant parameter measured using conventional rotational stimuli.Other parameters, such as the step asymmetry and measures related to theprobe component, go beyond what is available from conventional rotationtests and facilitate the identification of the side of the vestibularloss.

PSS Probe (or Sine) Component Measures:

The parameter called “sine component asymmetry” gives a comparison ofthe difference in VOR probe-component gains for rotations that evokeleftward eye movements versus rotations that evoke rightward eyemovements. The equation for the sine component asymmetry is shown inFIG. 17B relative to the graphs for the sine response during leftwardand rightward steps. This equation makes use of two VOR gain measuresdefined as:VOR _(L) =R _(L) /S _(L)VOR _(R) =R _(R) /S _(R),where:

-   -   R_(L)=peak slow phase eye velocity of the response (units °/s)        to the probe (or sine) component of the PSS stimulus during the        portion of the PSS when the step component is leftward-moving.    -   R_(R)=peak slow phase eye velocity of the response to the probe        (or sine) component of the PSS stimulus during the portion of        the PSS when the step component is rightward-moving.    -   S_(L)=peak amplitude the probe (or sine) component (units °/s)        of the PSS stimulus during the portion of the PSS when the step        component is leftward-moving.    -   S_(R)=peak amplitude the probe (or sine) component (units °/s)        of the PSS stimulus during the portion of the PSS when the step        component is rightward-moving.        Nominally, S_(R)=S_(L). The peak slow phase eye velocity values,        R_(L) and R_(R), are derived from a curve fit of a sinusoidal        function to the average probe-component eye velocity. The        expectation is that the sine component asymmetry parameter will        have a positive value for a patient with right side vestibular        loss, a negative value for a patient with left side vestibular        loss, and a value close to zero for subjects with normal        vestibular function.

The measures shown in FIGS. 17A-17B were used to determine responseparameter variation with PSS amplitude for the subjects of the PSSstimulus test. In the normal subjects, the step component asymmetry andsine component symmetry measures were tightly distributed about zero.The step component slopes were greater than 4°/s² for most normalsubjects, indicating that their VOR time constants were greater than 5s. Exceptions were on a normal subject with poor quality data (VORsuppression) and one overly tested normal subject.

For the unilateral loss subjects, the step component asymmetry and sinecomponent asymmetry measures generally indicated the side of vestibulardysfunction and were distinguishable from normal subject results evenwith the smallest amplitude PSS stimulus. Differences between normal andunilateral loss subjects increased with increasing PSS amplitude. Thestep component slopes were closer to zero than for most normal subjects,indicating that unilateral loss subjects have smaller VOR time constantscompared to normal subjects.

For the asymmetric bilateral loss subject, both step component and sinecomponent asymmetry measures indicated the side of greater vestibularloss, but the step component asymmetry measure showed larger deviationfrom normal. The step component slope measure was negative and lowerthan either normal or unilateral loss subjects, consistent with areduced VOR time constant (<5 s).

The results showed that the PSS rotation stimulus can reveal asymmetricVOR responses in subjects with unilateral and with asymmetric bilateralvestibular loss. Three VOR response measures were developed thatdistinguished between unilateral vestibular loss and normal subjects.Two of the measures were able to reliably identify the dysfunctionalear. The third VOR response measure provided information about the VORtime constant which is known to be reduced in unilateral vestibular losssubjects, and further reduced in bilateral vestibular loss subjects. Thelarge amplitude rotational motions required for the PSS stimulus werewell tolerated by all subjects. The large amplitude rotationstheoretically enhance ability to distinguish between normal andunilateral loss subjects, but also result in decreased accuracy of VORresponse estimates due to the presence of high frequency nystagmus. Itis likely that PSS stimuli with peak velocities in the range of150-225°/s will provide for optimal identification of asymmetricvestibular function.

A VOR Fixation Suppression Rotation Test Based on the Bias-ProbeRotation Test.

The same rotational stimuli (2-sine stimulus and PSS stimulus) that areused for the Bias-Probe rotation test performed in the dark can also beused with a visual fixation light. This version of the Bias-Proberotation test is performed using a single fixation light placed in frontof the subject, where this light rotates with the subject. The room inwhich this test is performed is otherwise dark. The purpose of using avisual fixation light is to partially suppress the eye movements evokedby the vestibulo-ocular reflex (VOR). The advantage of partiallysuppressing the VOR is that lower velocity eye movements are obtainedthat are often more consistent over time (compared to the VOR eyemovements obtained in the dark). VOR eye movements are “consistent” whenthey show a continuous relationship to the rotational stimulus velocity.More consistent eye movements provide more reliable measures that arebetter able to distinguish between normal and abnormal vestibularfunction.

Example eye movement data from two normal subjects are shown in FIGS.18A-18B. One of these normal subjects (middle trace of FIG. 18A) had“good” nystagmus (eye movements) during a PSS stimulus performed in thedark, and the other subject (lower trace of FIG. 18A) had “bad”nystagmus. The distinguishing feature of good versus bad nystagmus isthe consistency of the eye movements over time and the relationship ofthe eye movements to the stimulus rotation. When the test was repeatedwith the fixation light, the nystagmus was partially suppressed in thesubject with good nystagmus, but remained consistent over time (middletrace of FIG. 18B). When the test was repeated with the fixation lightfor the subject with bad nystagmus in the dark, the nystagmus becameconsistent over time (lower trace of FIG. 18B). Similar results areshown in FIGS. 19A-19B for two patients with a unilateral vestibularloss. The patient with a right unilateral loss (middle traces of FIGS.19A-19B) had consistent nystagmus on PSS tests performed in both thedark and with the fixation light. The patient with a left unilateralloss had inconsistent nystagmus in the dark (lower trace of FIG. 19A),but consistent nystagmus when tested with the fixation light (lowertrace of FIG. 19B).

Also evident in FIGS. 19A-19B showing the VOR with fixation for theunilateral vestibular loss patients, there is a large asymmetry betweeneye movements evoked during rotation to the left (positive PSS stimulusvelocity) versus rotation to the right (negative PSS stimulus velocity).The eye movements evoked by Bias-Probe rotation tests with fixation canbe analyzed using the same principles and methods developed for theanalysis of Bias-Probe rotation tests performed in the dark.Specifically, the slow-phase velocity eye movement responses to the biascomponent and the probe component can be separated from one another, andcurve fits performed to estimate parameters that characterize vestibularfunction and response symmetry. This applies for both the 2-sine and PSSrotational stimuli.

Unilateral vestibular loss patients show two types of VOR fixationasymmetries not present in normal subjects. First, unilateral vestibularloss patients are better able to visually suppress VOR eye movementsduring bias component rotation toward the dysfunctional ear than duringrotation toward the intact ear because the total change in semicircularcanal afferent nerve discharge rate is lower during rotation toward thedysfunctional ear than during rotation toward the intact ear. Second,VOR responses caused by the probe component are absent or reduced duringthe portion of the rotation stimulus when the patient is rotating towardthe dysfunctional ear because canal afferent activity is silenced in theintact ear and the dysfunctional ear is unable to encode the probecomponent stimulus.

Response parameters obtained from fixation test performed on subjectwith normal vestibular function and patients with unilateral vestibularloss subjects are shown in FIGS. 20A-20B. FIG. 20A shows a “stepcomponent asymmetry” measure that refers to a measure obtained from theresponse to the bias component of the PSS stimulus. FIG. 20B shows a“sine component asymmetry” measure that refers to a measure obtainedfrom the response to the probe component of the PSS stimulus. In nearlyall cases, these measures provided a good separation of normal subjectsfrom patients with a unilateral vestibular loss. The two cases were thesine component asymmetry measure did not provide a good separationbetween normal and unilateral loss are attributable to unilateral losssubjects who were able to nearly completely suppress their VOR using thefixation light.

CONCLUSION

The limitations with the current vestibular function tests indicate thatno single test thus far adequately answers the most important diagnosticquestions in the evaluation of vestibular function: (1) Is vestibularfunction normal or abnormal? (2). If abnormal, which ear is affected, orare both ears affected? (3) How severe is the abnormality? evaluatingvestibular response in the other ear of the subject relative to anothercomponent of the multiple component stimulus while vestibular responsein the one ear is turned off;

The inadequacy of the existing tests can be partially resolved byperforming multiple tests on the same patient, using a combination ofthe existing tests. However, some patients, due to their physicallimitations cannot tolerate certain of the tests (e.g. head pulse test),and in any case, multiple tests increase the cost of obtaining adiagnosis. In practice, physicians usually settle for a single test, andthe referred test has been the caloric test with all of its attendantlimitations.

Various embodiments for methods and apparatus according to the teachingsof the present invention provide rotation test and analysis thatovercome many of the poor performance features found in existing testsand provides a new diagnostic tool to identify normal and abnormalvestibular function, to localize an abnormality to a particular ear, andto evaluate the severity of the abnormality. This information iscritical for the physician s delivery of therapies targeted to thepatient's specific vestibular condition.

In embodiments, the use of rotational motions with amplitudes largerthan typically used in conventional clinical rotation tests can revealasymmetric VOR responses in subjects with unilateral vestibular loss.This VOR asymmetry can be reliably measured and used to identify thedysfunctional ear. The VOR asymmetry is revealed as a saturationnonlinearity during rotations towards the absent ear. Rotational motionsgreater than about 150°/s are sufficient to quantify the VOR saturationamplitude in unilateral loss subjects. The inclusion of a highfrequency, low amplitude probe component in the rotational stimulusprovides a second measure that identifies the presence and side ofabnormal vestibular functions. The larger amplitude rotational motionsrequired for the two-sine and PSS stimuli were well tolerated by testedsubjects. Optimal test sensitivity may be achieved when the head isoriented with the canal planes perpendicular to the rotation axis.However, it may be difficult to achieve this optimal orientation in eachsubject since external landmarks are not tightly correlated with canalorientation. Large amplitude rotations enhanced the ability todistinguish between normal and unilateral loss subjects, but alsoresulted in decreased accuracy of VOR response estimates due to thepresence of high frequency nystagmus. It is likely that a bias componentpeak velocity in the range of 150-200°/s will provide for optimalidentification of asymmetric vestibular function.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention. Although specificembodiments have been illustrated and described herein, it will beappreciated by those of ordinary skill in the art that any arrangementwhich is calculated to achieve the same purpose may be substituted forthe specific embodiment shown. This application is intended to cover anyadaptations or variations of the present invention. It is to beunderstood that the above description is intended to be illustrative,and not restrictive. Combinations of the above embodiments, and otherembodiments will be apparent to those of skill in the art upon reviewingthe above description. The scope of the invention includes any otherapplications in which the above structures and fabrication methods areused.

1. A method comprising: applying a multiple component stimulus tocontrol motion of a subject to turn off vestibular response in one earof the subject in response to a component of the multiple componentstimulus; evaluating vestibular response in the other ear of the subjectrelative to another component of the multiple component stimulus whilevestibular response in the one ear is turned off; evaluating vestibularresponse in the one ear with vestibular response in the other ear turnedoff; and analyzing the vestibular responses from each ear tocharacterize an asymmetry of an inner ear balance function.
 2. Themethod of claim 1, wherein turning off vestibular response in one earincludes applying a stimulus having a first component directed toessentially completely inhibit activity in a semicircular canal of theone ear.
 3. The method of claim 1, wherein applying a multiple componentstimulus includes applying a continuous, symmetric stimulus.
 4. Themethod of claim 1, wherein applying a multiple component stimulusincludes applying a stimulus with at least two components havingdifferent frequencies from each other.
 5. The method of claim 1, whereinapplying a multiple component stimulus includes applying a symmetricstimulus such that the one ear is inhibited and the other ear is excitedsubstantially simultaneously in a half cycle of the symmetric stimulusand the one ear is excited and the other ear is inhibited substantiallysimultaneously in another half cycle of the symmetric stimulus.
 6. Themethod of claim 1, wherein the method includes applying the multiplecomponent stimulus to provide cyclic control of activity in pair-wiseoriented semicircular canals in the ears such that one semicircularcanal is inhibited while the corresponding semicircular canal of thepair is excited.
 7. The method of claim 1, wherein evaluating vestibularresponse in the other ear of the subject relative to another componentof the multiple component stimulus includes modulating the componentapplied to turn off vestibular response in the one ear.
 8. The method ofclaim 1, wherein the method includes characterizing a semicircular canalasymmetry.
 9. A method comprising: applying a multiple componentstimulus to control motion of a subject to turn off vestibular responsein one ear of the subject in response to a first component of themultiple component stimulus; evaluating vestibular response in the otherear of the subject relative to a second component of the multiplecomponent stimulus while vestibular response in the one ear is turnedoff; evaluating vestibular response in the one ear with vestibularresponse in the other ear turned off; and analyzing the vestibularresponses from each ear to characterize an asymmetry of an inner earbalance function, wherein the first component is directed to essentiallycompletely inhibit activity in a semicircular canal of the one ear andthe second component is directed to probing a canal function of theother ear.
 10. The method of claim 9, wherein applying the stimulusincludes applying the stimulus to a device that rotates a seated subjectabout a vertical axis.
 11. The method of claim 9, wherein applying thestimulus includes applying the stimulus to a clinical rotation chair.12. A method comprising: turning off vestibular response in one ear of asubject; evaluating vestibular response in the other ear of the subject;evaluating vestibular response in the one ear with vestibular responsein the other ear turned off; and analyzing the vestibular responses fromeach ear to characterize an asymmetry of an inner ear balance function,wherein the method includes applying a stimulus to control motion of adevice that rotates the subject about an axis, the stimulus having abias component to control the motion of the device to temporarily turnoff vestibular response in the one ear of the subject and having a probecomponent to modulate the bias component while the vestibular responsein the one ear is turned off to evaluate responsiveness in the anotherear of the subject.
 13. The method of claim 12, wherein the methodfurther includes applying the stimulus in a substantially completelydark room.
 14. The method of claim 12, wherein the method furtherincludes applying the stimulus in a substantially dark room having anilluminated visual target.
 15. The method of claim 12, wherein applyinga stimulus includes applying the stimulus with the probe componenthaving a frequency higher than that of the bias component and anamplitude lower than that of the bias component.
 16. The method of claim12, wherein applying a stimulus includes applying the stimulus with thebias component of the stimulus including a sinusoidal waveform and theprobe component of the stimulus including a sinusoidal waveform.
 17. Themethod of claim 16, wherein applying the stimulus includes applying thestimulus with the bias component having a frequency less than or equalto 0.1 Hz and the probe component having a frequency of about 1 Hz. 18.The method of claim 16, wherein applying the stimulus includes applyingthe stimulus with the bias component having an amplitude between about150° per second peak velocity and about 250° per second peak velocity,and the probe component has an amplitude between about 10° per secondpeak velocity and about 20° per second peak velocity.
 19. The method ofclaim 12, wherein applying a stimulus includes applying the stimuluswith the bias component of the stimulus including an acceleration pulsewaveform and an acceleration step waveform and the probe component ofthe stimulus including a sinusoidal waveform.
 20. The method of claim19, wherein applying the stimulus includes applying the stimulus withthe probe component of the stimulus added to the acceleration stepwaveform of the bias component.
 21. The method of claim 19, whereinapplying the stimulus includes applying the stimulus with the biascomponent of the stimulus including the acceleration pulse waveformhaving a first duration and the acceleration step waveform having asecond duration, the second duration longer than the first duration. 22.The method of claim 21, wherein applying the stimulus includes applyingthe stimulus with the bias component of the stimulus including theacceleration pulse waveform having about a 400°/s² amplitude lastingabout 1 second and the acceleration step waveform having about a 30°/s²amplitude lasting about 4 seconds.
 23. The method of claim 22, whereinapplying the stimulus includes applying the stimulus with the probecomponent of the stimulus including the sinusoidal waveform having afrequency of about 1 Hz and an amplitude of about 20°/s peak velocityadded to the acceleration step waveform of the bias component.
 24. Themethod of claim 12, wherein the method further includes: isolating biasresponses to the bias component of the stimulus from probe responses tothe probe component of the stimulus; and analyzing separately the biasresponses and the probe responses.
 25. The method of claim 24, whereinisolating bias responses from probe responses includes measuring eyemovements resulting from applying the stimulus to control motion of thedevice.
 26. The method of claim 12 includes: computing eye velocity fromeye position data from the subject as a result of applying the stimulus;isolating a bias response to the bias component of the stimulus, thebias response isolated from a probe response to the probe component ofthe stimulus; and analyzing separately the bias response and the proberesponse.
 27. The method of claim 26, wherein the method furtherincludes obtaining a slow-phase eye velocity; bandpass filtering theslow-phase eye velocity to isolate the probe response providing abandpass slow-phase eye velocity; and parameterizing the probe response.28. The method of claim 27, wherein the method further includesaveraging the bandpass slow-phase eye velocity over a number of cyclesof the bias component and parameterizing the averaged bandpassslow-phase eye velocity.
 29. The method of claim 28, whereinparameterizing the averaged bandpass slow-phase eye velocity includesusing a curve fit of the averaged bandpass slow-phase eye velocity,<{dot over ({circumflex over (θ)}_(bp) the curve fit related to a probefrequency, ω_(p), and a bias frequency, ω_(b), and having a probecomponent eye velocity amplitude, A_(p), a probe component phase, φ_(p),a phase of the modulation waveform, φ_(b), and a modulation factor, m,that varies from 0 to 1, as fit parameters.
 30. The method of claim 29,wherein using a curve fit includes using the curve fit according to therelation<{dot over ({circumflex over (θ)}_(bp) >=A _(p)(1+m cos(ω_(b) t+φ_(b)))cos(ω_(p) t+φ _(p)).
 31. The method of claim 28, wherein thebandpass slow-phase eye velocity is averaged over five 0.1 Hz cycles.32. The method of claim 27, wherein bandpass filtering the slow-phaseeye velocity includes filtering the slow-phase eye velocity using abandpass filter of about 0.5 Hz to about 5 Hz.
 33. The method of claim26, wherein the method further includes obtaining a slow-phase eyevelocity and a stimulus velocity; low-pass filtering the slow-phase eyevelocity to remove the probe component providing a low-pass slow-phaseeye velocity; low-pass filtering the stimulus velocity to remove theprobe component providing a low-pass stimulus velocity; and obtaining aninput-output function correlated to the low-pass slow-phase eye velocityversus the low-pass stimulus velocity.
 34. The method of claim 33,wherein the method further includes averaging the low-pass slow-phaseeye velocity and the low-pass stimulus velocity over a number of cyclesof the bias component.
 35. The method of claim 34, wherein obtaining aninput-output function includes: estimating a phase for the averagedlow-pass stimulus velocity and a phase for the averaged low-passslow-phase eye velocity at a frequency of the bias component; and timeshifting the averaged low-pass stimulus velocity and the averagedlow-pass slow-phase eye velocity such that the two are aligned with a180° phase shift between them, after estimating the phase for theaveraged low-pass stimulus velocity and the phase for the averagedlow-pass slow-phase eye velocity.
 36. The method of claim 35, whereinthe method further includes determining a curve fit to the averagedlow-pass slow-phase eye velocity, <{dot over ({circumflex over(θ)}′_(lp)>, related to the averaged low-pass stimulus velocity,<ω′_(lp)>, the curve fit having fit parameters K related to gainbehavior of the input-output function and β related to a saturationbehavior of the input-output function.
 37. The method of claim 35,wherein determining a curve fit includes determining the curve fitaccording to the relation$\left\langle {\hat{\overset{.}{\theta}}}_{lp}^{\prime} \right\rangle = {\frac{K\left( {1 - {\mathbb{e}}^{{- \beta}{\langle\omega_{lp}^{\prime}\rangle}}} \right)}{1 + {\mathbb{e}}^{{- \beta}{\langle\omega_{lp}^{\prime}\rangle}}}.}$38. The method of claim 33, wherein low-pass filtering the slow-phaseeye velocity includes filtering the slow-phase eye velocity using alow-pass filter having about a 0.5 Hz cutoff.
 39. The method of claim33, wherein the low-pass slow-phase eye velocity is averaged over five0.1 Hz cycles.
 40. The method of claim 33, wherein the method furtherincludes determining deviations of the input-output function from astraight line.
 41. The method of claim 12, wherein applying a stimulusincludes applying a pulse-step-sine stimulus and collecting averageslow-phase eye velocity data.
 42. The method of claim 41, wherein themethod includes generating a comparison of a difference in response gainfor rotations that evoke leftward eye movements versus rotations thatevoke rightward eye movements.
 43. The method of claim 42, whereingenerating the comparison includes generating a step asymmetry parameterbased on an average stimulus velocity (A_(SL)) during a leftward-movingstep portion of the pulse-step-sine stimulus, an average stimulusvelocity (A_(SR)) during a rightward-moving step portion of thepulse-step-sine stimulus, an average vestibulo-ocular reflex (VOR)slow-phase eye velocity (A_(RL)) during the leftward-moving step portionof the pulse-step-sine stimulus, and an average VOR slow phase eyevelocity (A_(RR)) during the rightward-moving step portion of thepulse-step-sine stimulus.
 44. The method of claim 43, wherein generatinga step asymmetry parameter includes generating the step asymmetryparameter correlated to((A_(RL)/A_(SL))−(A_(RR)/A_(SR)))/((A_(RL)/A_(SL))+(A_(RR)/A_(SR))). 45.The method of claim 41, wherein the method includes generating a measurerelated to a vestibulo-ocular reflex (VOR) time constant.
 46. The methodof claim 45, wherein generating the measure includes generating a meanresponse slope parameter related to a rate-of-change (S_(RR)) ofslow-phase eye velocity measured during a rightward-moving step portionof the pulse-step-sine stimulus and a rate-of-change (S_(RL)) ofslow-phase eye velocity measured during a leftward-moving step portionof the pulse-step-sine stimulus and correlated to (S_(RR)−S_(RL))/2. 47.The method of claim 41, wherein the method includes generating acomparison of a difference in vestibulo-ocular reflex (VOR)probe-component gains for rotations that evoke leftward eye movementsversus rotations that evoke rightward eye movements.
 48. The method ofclaim 47, wherein the method includes generating two VOR gain measuresrelated to a peak slow-phase eye velocity (R_(L)) of a response to thesine component of the pulse-step-sine stimulus during a portion of thepulse-step-sine stimulus when the step component is leftward-moving, apeak slow phase eye velocity (R_(R)) of the response to the sinecomponent of the pulse-step-sine stimulus during a portion of thepulse-step-sine stimulus when the step component is rightward-moving, apeak amplitude (S_(L)) of the sine component of the pulse-step-sinestimulus during the portion of the pulse-step-sine stimulus when thestep component is leftward-moving, and a peak amplitude (S_(R)) of thesine component of the pulse-step-sine stimulus during the portion of thepulse-step-sine stimulus when the step component is rightward-moving,according to the relationsVOR _(L) =R _(L) /S _(L)VOR _(R) =R _(R) /S _(R.)
 49. The method of claim 48, wherein the methodincludes generating a sine component gain asymmetry parameter correlatedto the relation(VOR_(L)−VOR_(R))/(VOR_(L)+VOR_(R)).
 50. A computer-readable mediumhaving computer-executable instructions for performing a method, themethod comprising: applying a multiple component stimulus to controlmotion of a subject to turn off vestibular response in one ear of thesubject in response to a component of the multiple component stimulus;evaluating vestibular response in the other ear of the subject relativeto another component of the multiple component stimulus while vestibularresponse in the one ear is turned off; evaluating vestibular response inthe one ear with vestibular response in the other ear turned off; andanalyzing the vestibular responses from each ear to characterize anasymmetry of an inner ear balance function.
 51. The computer-readablemedium of claim 50, wherein applying a multiple component stimulusincludes applying a continuous, symmetric stimulus.
 52. Thecomputer-readable medium of claim 50, wherein applying a multiplecomponent stimulus includes applying a stimulus with at least twocomponents having different frequencies from each other.
 53. Thecomputer-readable medium of claim 50, wherein applying a multiplecomponent stimulus includes applying a symmetric stimulus such that theone ear is inhibited and the other ear is excited substantiallysimultaneously in a half cycle of the symmetric stimulus and the one earis excited and the other ear is inhibited substantially simultaneouslyin another half cycle of the symmetric stimulus.
 54. Thecomputer-readable medium of claim 50, wherein the method includesapplying the multiple component stimulus to provide cyclic control ofactivity in pair-wise oriented semicircular canals in the ears such thatone semicircular canal is inhibited while the corresponding semicircularcanal of the pair is excited.
 55. The computer-readable medium of claim50, wherein evaluating vestibular response in the other ear of thesubject relative to another component of the multiple component stimulusincludes modulating the component applied to turn off the vestibularresponse in the one ear.
 56. The computer-readable medium of claim 50,wherein analyzing the vestibular responses from each ear to characterizean asymmetry of an inner ear balance function includes characterizing asemicircular canal asymmetry.
 57. A computer-readable medium havingcomputer-executable instructions for performing a method, the methodcomprising: turning off vestibular response in one ear of a subject;evaluating vestibular response in the other ear of the subject;evaluating vestibular response in the one ear with vestibular responsein the other ear turned off; analyzing the vestibular responses fromeach ear to characterize an asymmetry of an inner ear balance function;and applying a stimulus to control motion of a device that rotates thesubject about an axis, the stimulus having a bias component to controlthe motion of the device to temporarily turn off vestibular response inthe one ear of the subject and having a probe component to modulate thebias component while the vestibular response in the one ear is turnedoff to evaluate responsiveness in the other ear of the subject.
 58. Thecomputer-readable medium of claim 57, wherein applying a stimulusincludes applying the stimulus with the probe component having afrequency higher than that of the bias component and an amplitude lowerthan that of the bias component.
 59. The computer-readable medium ofclaim 57, wherein applying a stimulus includes applying the stimuluswith the bias component of the stimulus including a sinusoidal waveformand the probe component of the stimulus including a sinusoidal waveform.60. The computer-readable medium of claim 59, wherein applying thestimulus includes applying the stimulus with the bias component having afrequency less than or equal to 0.1 Hz and the probe component having afrequency of about 1 Hz.
 61. The computer-readable medium of claim 57,wherein applying a stimulus includes applying the stimulus with the biascomponent of the stimulus including an acceleration pulse waveform andan acceleration step waveform and the probe component of the stimulusincluding a sinusoidal waveform.
 62. The computer-readable medium ofclaim 61, wherein applying the stimulus includes applying the stimuluswith the probe component of the stimulus added to the acceleration stepwaveform of the bias component.
 63. The computer-readable medium ofclaim 61, wherein applying the stimulus includes applying the stimuluswith the bias component of the stimulus including the acceleration pulsewaveform having a first duration and the acceleration step waveformhaving a second duration, the second duration longer than the firstduration.
 64. The computer-readable medium of claim 57, wherein thecomputer-executable instructions for performing the method furtherinclude: isolating bias responses to the bias component of the stimulusfrom probe responses to the probe component of the stimulus; andanalyzing separately the bias responses and the probe responses.
 65. Thecomputer-readable medium of claim 64, wherein isolating bias responsesfrom probe responses includes measuring eye movements resulting fromapplying the stimulus to control motion of the device.
 66. Thecomputer-readable medium of claim 57, wherein the computer-readablemedium has computer-executable instructions for performing a methodcomprising: obtaining eye velocity generated from eye position data fromthe subject as a result of applying the stimulus; isolating a biasresponse to the bias component of the stimulus, the bias responseisolated from a probe response to the probe component of the stimulus;and analyzing separately the bias response and the probe response. 67.The computer-readable medium of claim 66, wherein thecomputer-executable instructions for performing the method furtherinclude parameterizing a bandpass slow-phase eye velocity generated fromisolating the probe response with respect to an acquired slow-phase eyevelocity by bandpass filtering the slow-phase eye velocity.
 68. Thecomputer-readable medium of claim 67, wherein parameterizing a bandpassslow-phase eye velocity includes parameterizing an averaged bandpassslow-phase eye velocity obtained from averaging the bandpass slow-phaseeye velocity over a number of cycles of the bias component.
 69. Thecomputer-readable medium of claim 68, wherein parameterizing theaveraged bandpass slow-phase eye velocity includes using a curve fit ofthe averaged bandpass slow-phase eye velocity, <{dot over ({circumflexover (θ)}_(bp)>, the curve fit related to a probe frequency, ω_(p), anda bias frequency, ω_(b), and having a probe component eye velocityamplitude, A_(p), a probe component phase, φ_(p), a phase of themodulation waveform, φ_(b), and a modulation factor, m, that varies from0 to 1, as fit parameters.
 70. The computer-readable medium of claim 69,wherein using a curve fit includes using the curve fit according to therelation<{dot over ({circumflex over (θ)}_(bp) >=A _(p)(1+m cos(ω_(b) +φ_(b)))cos(ω_(p) +t+φ _(p)).
 71. The computer-readable medium of claim66, wherein the computer-executable instructions for performing themethod further include obtaining an input-output function correlated toa low-pass slow-phase eye velocity versus a low-pass stimulus velocity,the low-pass slow-phase eye velocity generated from low-pass filtering aslow-phase eye velocity, the low-pass stimulus velocity generated fromlow-pass filtering a stimulus velocity of the stimulus.
 72. Thecomputer-readable medium of claim 71, wherein the input-output functionis correlated to an averaged low-pass slow-phase eye velocity and anaveraged low-pass stimulus velocity, the averaged low-pass slow-phaseeye velocity and the averaged low-pass stimulus velocity obtained byaveraging the low-pass slow-phase eye velocity and the low-pass stimulusvelocity over a number of cycles of the bias component.
 73. Thecomputer-readable medium of claim 72, wherein the computer-executableinstructions for performing the method further include: estimating aphase for the averaged low-pass stimulus velocity and a phase for theaveraged low-pass slow-phase eye velocity at a frequency of the biascomponent; and time shifting the averaged low-pass stimulus velocity andthe averaged low-pass slow-phase eye velocity such that the two arealigned with a 180° phase shift between them, after estimating the phasefor the averaged low-pass stimulus velocity and the phase for theaveraged low-pass slow-phase eye velocity.
 74. The computer-readablemedium of claim 73, wherein the computer-executable instructions forperforming the method further include, after time shifting the averagedlow-pass stimulus velocity and the averaged low-pass slow-phase eyevelocity, determining a curve fit to the averaged low-pass slow-phaseeye velocity, <{dot over ({circumflex over (θ)}′_(lp)>, related to theaveraged low-pass stimulus velocity, <ω′_(lp)>, the curve fit having fitparameters K related to gain behavior of the input-output function and βrelated to a saturation behavior of the input-output function.
 75. Thecomputer-readable medium of claim 74, wherein determining a curve fitincludes determining the curve fit according to the relation$\left\langle {\hat{\overset{.}{\theta}}}_{lp}^{\prime} \right\rangle = {\frac{K\left( {1 - {\mathbb{e}}^{{- \beta}{\langle\omega_{lp}^{\prime}\rangle}}} \right)}{1 + {\mathbb{e}}^{{- \beta}{\langle\omega_{lp}^{\prime}\rangle}}}.}$76. The computer-readable medium of claim 71, wherein thecomputer-executable instructions for performing the method furtherinclude determining deviations of the input-output function from astraight line.
 77. The computer-readable medium of claim 57, whereinapplying a stimulus includes applying a pulse-step-sine stimulus andcollecting average slow-phase eye velocity data.
 78. Thecomputer-readable medium of claim 77, wherein the computer-executableinstructions for performing the method include generating a comparisonof a difference in response gain for rotations that evoke leftward eyemovements versus rotations that evoke rightward eye movements.
 79. Thecomputer-readable medium of claim 78, wherein generating the comparisonincludes generating a step asymmetry parameter based on an averagestimulus velocity (A_(SL)) during a leftward-moving step portion of thepulse-step-sine stimulus, an average stimulus velocity (A_(SR)) during arightward-moving step portion of the pulse-step-sine stimulus, anaverage vestibulo-ocular reflex (VOR) slow-phase eye velocity (A_(RL))during the leftward-moving step portion of the pulse-step-sine stimulus,and an average VOR slow phase eye velocity (A_(RR)) during therightward-moving step portion of the pulse-step-sine stimulus.
 80. Thecomputer-readable medium of claim 79, wherein generating a stepasymmetry parameter includes generating the step asymmetry parametercorrelated to((A_(RL)/A_(SL))−(A_(RR)/A_(SR)))/((A_(RL)/A_(SL))+(A_(RR)/A_(SR))). 81.The computer-readable medium of claim 77, wherein thecomputer-executable instructions for performing the method includegenerating a measure related to a vestibulo-ocular reflex (VOR) timeconstant.
 82. The computer-readable medium of claim 81, whereingenerating the measure includes generating a mean response slopeparameter related to a rate-of-change (S_(RR)) of slow-phase eyevelocity measured during a rightward-moving step portion of thepulse-step-sine stimulus and a rate-of-change (S_(RL)) of slow-phase eyevelocity measured during a leftward-moving step portion of thepulse-step-sine stimulus and correlated to (S_(RR)−S_(RL))/2.
 83. Thecomputer-readable medium of claim 77, wherein the computer-executableinstructions for performing the method include generating a comparisonof a difference in vestibulo-ocular reflex (VOR) probe-component gainsfor rotations that evoke leftward eye movements versus rotations thatevoke rightward eye movements.
 84. The computer-readable medium of claim83, wherein the computer-executable instructions for performing themethod include generating two VOR gain measures related to a peakslow-phase eye velocity (R_(L)) of a response to the sine component ofthe pulse-step-sine stimulus during a portion of the pulse-step-sinestimulus when the step component is leftward-moving, a peak slow phaseeye velocity (R_(R)) of the response to the sine component of thepulse-step-sine stimulus during a portion of the pulse-step-sinestimulus when the step component is rightward-moving, a peak amplitude(S_(L)) of the sine component of the pulse-step-sine stimulus during theportion of the pulse-step-sine stimulus when the step component isleftward-moving, and a peak amplitude (S_(R)) of the sine component ofthe pulse-step-sine stimulus during the portion of the pulse-step-sinestimulus when the step component is rightward-moving, according to therelationsVOR _(L) =R _(L) /S _(L)VOR _(R) =R _(R) /S _(R.)
 85. The computer-readable medium of claim 84,wherein the computer-executable instructions for performing the methodinclude generating a sine component gain asymmetry parameter correlatedto the relation(VOR_(L)−VOR_(R))/(VOR_(L)+VOR_(R)).